NZ264516A

NZ264516A - Benzodiazepine and benzothiazepine derivatives and analogues; medicaments

Info

Publication number: NZ264516A
Application number: NZ264516A
Authority: NZ
Inventors: Hidefumi Yukimasa; Ryuichi Tozawa; Yasuo Sugiyama; Masakuni Kori
Original assignee: Takeda Chemical Industries Ltd
Priority date: 1993-09-24
Filing date: 1994-09-22
Publication date: 1998-02-26
Also published as: HUT70962A; EP0645378A1; NO943495D0; CA2132792A1; CN1106397A; EP0645377B1; HU9402739D0; NO306063B1; NO943495L; US5677298A; PH31660A; AU678503B2; DE69404924D1; FI944418A0; DE69425615D1; US5698691A; ATE195732T1; CA2132794A1; CN1054380C; RU2129547C1

Abstract

Disclosed is a squalene synthetase inhibitor which comprises the compound represented by the formulawherein R₁ is hydrogen or an optionally substituted hydrocarbon group; R₂ is hydrogen, an optionally substituted alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X' is a substituent comprising an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, an optionally substituted amino group or an optionally substituted heterocyclic radical having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Ring J' is a 7- to 8-membered heterocyclic ring containing at most three ring constituting hetero atoms; D is C or N; the Ring J' optionally having, besides R₁, R₂ and X', a further substituent; provided that the condensed ring composed of Ring A and ring J' is not a 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring, or a pharmaceutically acceptable salt thereof, and which is useful for the prophylaxis or therapy of hypercholesteremia or coronary sclerosis of mammals.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £64516 New Zealand No. International No. 264516 PCT/ TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 24.09.1993;28.09.1993; Complete Specification Filed: 22.09.1994 Classification:^) C07D281/10; C07D243/14,16,18,24; C07D267/14; C07D223/16; C07D255/04; C07D498/02.04; A61K31/55.395 Publication date: 24 February 1998 Journal No.: 1425 Title of Invention: Condensed cyclic compounds and their use Name, address and nationality of applicant(s) as in international application form: TAKEDA CHEMICAL INDUSTRIES, LTD., a Japanese company of 1-1, Doshomachi 4-chome, Chuo-ku, Osaka 541, Japan NEW ZEALAND PATENTS ACT 1953 complete specification 26 45 1 6 Patents Form No. 5 Our Ref: DT203722 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION CONDENSED CYCLIC CQMPOUNDS AND TEDBIR USB We, TAKEDA CHEMICAL INDUSTRIES, LTD., a Japanese company of 1-1, Doshcwachi 4-chome, Chuo-Ku, Osaka 541, Japan, hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement s PT0535356 - 1 - (followed by page la) - 3a - 2 § 4 5 | Condensed cyclic compounds and their use Field of the invention This invention relates to a condensed cyclic compound or a salt thereof, and, to a squalene synthetase inhibitor comprising same as the effective component. Background of the invention Hypercholesteremia, high blood pressure and smoking are known as three major dangerous factors of causing ischemic heai^t diseases. Adequate control of cholesterol concentration in blood is remarkably important for the prophylaxis or therapy of, besides these ischemic heart diseases, as well as of coronary sclerosis. As pharmaceutical compositions for lowering cholesterol in blood, attention has been drawn to those for controlling the biosynthesis of cholesterol, besides those of inhibiting its absorption by binding bile acid including, among others, cholestyramine, colestipol (disclosed in, for example, USP 4027009), and those of suppressing the intestinal absorption of •cholesterol by inhibiting acyl coenzyme A cholesterol acyl transferase (ACAT) including melinamide (disclosed in French Patent No.1476569). As pharmaceutical preparations for.controlling the biosynthesis of cholesterol, lovastatin (disclosed in USP 4231938), simvastatin (disclosed in USP 4444784), pravastatin (USP 4346227), etc., which are capable of inhibiting especially 3-hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase, are provided for> medicinal use. However, when HMG-CoA reductase is inhibited, not only the biosynthesis of cholesterol but the biosynthesis, of some other components such ubiquinone, dolichol and heme A, which are necessary for the living -body, is also inhibited, s.o that occurrences of undesirable side (followed by page 2) - 2 - 2 6 4 5 1 $ ' u effects to be caused thereby are feared. Squalene synthetase is an enzyme taking part in the essential step of new cholesterol biosynthetic route. And, this enzyme is an enzyme forming squalene 5 catalyzing the reductive dimerization of two molecules of farnesyl pyrophosphoric acid. On the other hand, the compounds expected as inhibitors of cholesterol biosynthesis by inhibiting squalene synthetase are disclosed in Journal of 10 Medicinal Chemistry, Vol. 51, No. 10, pp.1869-1871, 1988, Japanese published unexamined patent application No. Hl-213288/1989 (JPA HI(1989)-213288), JPA H2(1990)-1010a8, JPA H2(1990)-235820, JPA H2(1990)-235821, JPA H3(1991)-20226, JPA H3(1991)-68591, JPA H3(1991)-148288 .15 and USP 5,019,390, USP5 ,135, 935 , W09215579, WO9309155 and W09313096. And, various compounds showing antifungal action by inhibiting the synthesis of squalene have been known (JPA H4(1992)-279589, EP-475706, EP-494622, EP-503520, 2 0 among others). In reference to 2-oxo-2,3,4,5-tetrahydro-lH-[l]-benzazepine derivatives, disclosure is found in J. Med. Chem., 14., 849(1971), Chem. Pharm. Bull., 38, 3331(1990), J. Chem. Soc. PERKIN TRANS. 1, 353 (1991) 25 and J. Med. Chem., 14, 40(1971). In reference to 2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine derivatives, disclosure is found in J. Prakt. Chem., 36., 5(1967), Arch. Pharm. 300. 299(1967) and USP 3463774. 30 2,3-Dihydro-2-oxo-lH-l,4-benzodiazepine derivatives, in which the the 3-position is occupied with an alkyl group substituted with ester, carboxylic acid or carbamoyl, and, further, the 5-position is occupied with an aryl group are disclosed in J. 35 Heterocycl. Chem. 27., 631(1990), JPA S63(1988)-246666, Bull. Chim. Farm., 113. 642(1974), J. Chem. Soc., Chem. - 3 - e 6 4 5 Commun., 1973, 721, J. Org. Chem., 38, 3502(1973) and Journal of the Takeda Research Laboratories, 29, 134(1970). In reference to 2-oxo-2,3,5,6-tetrahydro-lH-4,l-benzoxazocine derivatives, disclosure is found in Chem. Pharm. Bull., 34(1)> 140(1986). In reference to 2,4-dioxo-2,3,4,5-tetrahydro-lH-1,5-benzodiazepine derivatives, disclosure is found in "Heterocyclic Compounds" ed by R. Ian Fryer (1991) John Wiley & Sons, Inc. p.p 289-313. In reference to 2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepine derivatives, disclosure is found in Japanese published examined patent application No. S45-11148/1970 (JPB S45(1970)-11148). In reference to 2-oxo-l,2,4,5-tetrahydro-3H-l,3-benzodiazepine derivatives, disclosure is found in J. Chem. Soc., Perkin Trans. 1(12), 1331 (1976) and French Patent No. 2528838. Object of the invention Ubiquinone, dolichol and heme A have been known as being synthesized from famesyl pyrophosphate along the cholesterol biosynthesis pathway. Therefore, for avoiding occurrence of side effects due to loss of these substances, it is desirable to inhibit enzyme systems subsequent to farnesyl pyrophosphate, especially squalene synthetase, in the cholesterol biosynthetic pathway. Summary of the invention The present inventors have, taking the above-mentioned circumstances into consideration, made diligent research work, and found that the condensed cyclic compounds have an excellent action of inhibiting squalene synthetase, thus the present invention being accomplished. More specifically, the present invention is to provide 264516 (1) A compound of the formula (I): \ , /——Zj GXh i-r CI) r/ wherein Rx is hydrogen or an optionally substituted hydrocarbon group; R2' is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X1 is a group represented by the formula X-Y wherein X is a bond or a divalent atomic chain represented by the formula ^J12V~E~^CH^rT" wherein m and n independently denote 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHC0-, -CON(R5)- or -NHCONH-; wherein R4 and R5 independently stand for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group, when n is 2 or 3 each R4 may be the same or different; and R3 stands for H, a lower alkyl group, aralkyl group or acyl group; Y is (i) an optionally esterified carboxyl group; (ii) an optionally substituted carbamoyl group (iii) an hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted aryloxy group or an optionally substituted aralkyloxy group; (iv) an optionally substituted amino group; or (v) an optionally substituted heterocyclic radical having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Ring is a 7-membered heterocyclic ring containing at most three ring constituting hetero atoms; D is optionally substituted (followed N.Z. py p?sf 1?$ I9S5 264516 4a C or N; Z^ is optionally substituted C, N( C=0, S(0)q (q=0, 1 or 2) or 0; D-Z^ may be a single bond or a double bond; K is optionally substituted C or N; the ring Ji optionally having, besides R^, R2' and X', a further substituent, provided that the condensed ring composed of Ring A and Ring is not 2-oxo-l, 2, 3,5-tetrahydro-4,1-benzoxazepine ring, 2-oxo-l,4-benzodiazepine, 1,4-benzodiazepine ring or 2,4-dioxo-2,3,4,5-tetrahydro-lH-1,5-benzodiazepine ring, or a salt thereof, (2) The compound ,or the salt thereof as mentioned in the item (1) , in which the compound is represented by the formula (!'): (followed by page 5) - 5 - 264516 U Qjt\-r <i') Ri wherein Ri is hydrogen or an optionally substituted hydrocarbon group; R2' is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X' is a group represented by the formula X-Y wherein X is a bond or a divalent atomic chain represented by the formula —^CH2 *m~E~ ^ CH^rT" wherein m and n independently denote 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHC0-, -CON(R5)- or -NHCONH-; wherein R4 and R5 independently stand for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group, when n is 2 or 3 each R4 may be the same or different; and R3 stands for H, a lower alkyl group, aralkyl group or acyl group; Y is (i) an optionally esterified carboxyl group; (ii) an optionally substituted carbamoyl group; (iii) an hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted aryloxy group or an optionally substituted aralkyloxy group; (iv) an optionally substituted amino group; or (v) an optionally substituted heterocyclic radical having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Ring J2 is a 7-membered heterocyclic ring; Z2 is S(0)g (q=-0, 1 or 2) , optionally substituted C, C=0, or O; K is optionally substituted C or N; G is 0 or S, provided that the condensed ring composed of Ring A and Ring J2 is not tetrahydro-4,1-benzoxazepine ring, or a salt t-hereof7 i 1 D~C ?5S5 {followed by pajga Sa-)—- - 264516 5a (3) A squalene synthetase inhibitor which comprises the compound represented by the formula (I): wherein Rx is hydrogen or an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X' is a group represented by the formula X-Y wherein X is a bond or a divalent atomic chain N represented by the formula —^CH2 ^m~E~ ^ CH^n"~ wherein m and n independently denote 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHC0-, -CON(R5)~ or -NHCONH-; wherein R4 and R5 independently stand for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group, when n is 2 or 3 each R4 may be the same or different; and R3 stands for H, a lower alkyl group, aralkyl group or acyl group; CI) hydrocarbon group; R2' is an optionally substituted N.Z. PAT^ 264516 6 - Y is (i) an optionally esterified carboxyl group; (ii) an optionally substituted carbamoyl group; (iii) an hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted aryloxy group or an optionally substituted aralkyloxy group; (iv) an optionally substituted amino group; or (v) an optionally substituted heterocyclic radical having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Ring Jq_ is a 7-membered heterocyclic ring containing at most three ring constituting hetero atoms; D is optionally substituted C or N; Z2. is optionally substituted C, N, C=0, S(0)g (q=0, l or 2) or 0; D-Z^ may be a single bond or a double bond; K is optionally substituted C or N; the ring Jn optionally having, besides R]_, R2' and X' , a further substituent, provided that the condensed ring composed of Ring A and Ring J 3. is not 2-oxo-l,2,3,5-tetrahydro-4,1-benzoxazepine ring, 2-oxo-l,4-benzodiazepine, 1,4-benzodiazepine ring or 2,4-dioxo-2,3,4,5-tetrahydro-lH-1,5-benzodiazepine ring, or a pharmaceutically acceptable salt thereof, (4) The inhibitor as mentioned in the item (3), in which the compound is represented by the formula (I"'): k/ (followed hy T3norr»-f6a) "VTz^PATitNT 11 OEC 1995 264516 - 6a - wherein Rj is hydrogen or an optionally substituted hydrocarbon group; R2 is hydrogen, an optionally substituted alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X^ is a bond or a divalent atomic chain represented by the formula R4 —fCH_ ) -E-( CH-)— ^ m n wherein m and n independently denote 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHCO-, -CON(R5)- or -NHCONH-; wherein R4 and R5 independently stand for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group, when n is 2 or 3 each R4 may be the same or different; and R3 stands for H, a lower alkyl group, aralkyl group or acyl group. Y is (i) an optionally esterified carboxyl group; (ii) an optionally substituted carbamoyl group; (iii) a hydroxyl group an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted aryloxy group; (iv) an optionally substituted amino group; or (v) an optionally substituted heterocyclic radical having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an (followed by page 7) N.Z. PATENT r r;r 2 1 OEC 1395 - 7 - 26 4 510 optionally substituted aromatic heterocyclic ring; Z3 is =N-, -N(R7)- (wherein R7 stands for H, alkyl group or acyl group), -S-, -S(O)-, -S(0)2~, -CH2- or -0-; G is 0 or S; the symbol is a double bond when Z3 is =N-, while a single bond when Z3 is not =N-, provided that, when Z3 is -0— and Ring A is an optionally substituted benzene ring, G is S, or a pharmaceutical^ acceptable salt thereof, and 5^, (5) the use of a compound of the formula (I ) \~r • N ( wherein Rx is hydrogen or an optionally substituted hydrocarbon group; R2' is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X' is a group represented by the formula X-Y wherein X is a bond or a divalent .atomic chain represented by the formula —^CH2 CH^rT~ ; wherein m and n independently denote 0, 1, 2 or 3; E stands for a bo^d or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHC0-, -CON(R5)- or -NHCONH-; wherein R4 and R5 independently stand for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an" optionally substituted phenyl group, when n is 2 or 3 eac'ii R4 may be the same or different; and R3 stands for H, a ' lower alkyl group, aralkyl group or acyl group; / Y is (i) an optionally esterified carboxyl group; f (ii) an optionally substituted carbamoyl group^; (iii) an hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted aryloxy group or an optionally substituted aralkyloxy group; / j (iv) an optionally substituted amino 9ro^^||9gtuai Property Office of NZ - 6 JAN 1998 . . ll/pn 264 516 - 7a - (v) an optionally substituted heterocyclic radical • having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Ring is a 7-membered heterocyclic ring containing at most three ring constituting hetero atoms; D is optionally substituted C or N; Zx is optionally substituted c, N, C=0, S(0)g (q=0, 1 or 2) or 0; D-Z]_ may be a single bond or a double bond; K is optionally substituted C or N; the ring J]_ optionally having, besides R^, R2' and X', a further substituent, provided that the condensed ring composed of Ring A and Ring Ji is not 2-oxo-l,2,3,5-tetrahydro-4,1-benzoxazepine ring, 2-oxo-l,4-benzodiazepine, 1,4-benzodiazepine ring or 2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine ring; or a pharraaceutically acceptable salt thereof, in the manufacture of a medicament for use as a squalene synthetase inhibitor- Intellectual Property Office of NZ - 6 JAN 1998 Received (followed by page 7b) 264 5 1i - 7b - Further, the present invention is to provide a method of producing a novel compound represented by the formula (I) or a salt thereof. Detailed description of the invention In the above formulae (I), (I'), (I") and (I'''), as the hydrocarbon group of the "optionally substituted hydrocarbon groups" shown by Rw mention is made of aliphatic chain-like hydrocarbon groups, alicyclic hydrocarbon groups and aryl groups, etc., among them, aliphatic chain-like hydrocarbon groups being preferable. As the aliphatic chain-like hydrocarbon groups of said hydrocarbon groups, mention is made of, for example, straight-chain or branched aliphatic hydrocarbon groups, such as alkyl group,, alkenyl group, alkynyl group, etc., among them, alkyl groups being preferable. As the alkyl group, mention is made of, for example, Cx_7 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, etc., and, among them, C3.3 alkyl groups such as n-propyl, isopropyl, isobutyl, neopentyl, etc. are preferable, further, isobutyl, neopentyl being preferable. As the said alkenyl group, mention is made of, for example, C2_g alkenyl such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-l- (followed by page 8) - 8 - 2 6 4 5 propenyl, 2-methyl-2-propenyl/ 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc., and, among them, vinyl, allyl, isopropenyl, 2-methylallyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, etc. . are especially preferable. As the said alkynyl group, mention is made of, for example-, C2.6 alkynyl such-as - — ethynyl, 1-propynyl, 2-propynyl,' 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynylr 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hex-ynyl, etc., and, among them, ethynyl, 1-propynyl, 2-propynyl, etc. are especially preferable. Examples of the alicyclic hydrocarbon groups of said hydrocarbon group include saturated or unsaturated alicyclic hydrocarbon groups such as cycloalkyl group, cycloalkenyl group, cycloalkadienyl group, etc. As said cycloalkyl group, C3,g cycloalkyl groups are preferable, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc. are mentioned, and, among them, C3_6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. are preferable. As said cycloalkenyl group, mention is made of, for example, 2-cyclopenten-l-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl, 3-cyclohexen-l-yl, 1-cyclobuten-l-yl, 1-cyclopenten-l-yl, etc. As said cycloalkadienyl group, mention is made of, for example, 2,4-cyclopentadien-l-yl, 2,4-cyclohexadien-l-yl, 2,5-cyclohexadien-l-yl, etc. As the aryl group of said hydrocarbon group, mention is made of mono-cyclic or condensed polycyclic aromatic hydrocarbon groups, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc., and, among them, phenyl, 1-naphthyl, 2-naphthyl, etc. . s - 26 4 are especially preferable. As substituents of the "optionally substituted hydrocarbon groups " shown by Rt, mention is made of optionally substituted aryl groups, optionally substituted cycloalkyl groups or cycloalkenyl groups, optionally substituted heterocyclic groups, optionally substituted amino groups, optionally substituted hydroxyl groups, optionally substituted thiol groups, halogen (e.g. fluorine, chlorine, bromine, iodine), oxo, etc., and, the hydrocarbon group shown by Rj is optionally substituted with 1 to 5 (preferably 1 to 3) of these substituents at any possible position. As aryl-groups of said optionally substituted aryl groups, mention is made of phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc., and, among them, phenyl, 1-naphthyl and 2-naphthyl are preferable. As substituents of said optionally substituted aryl, mention is made of Ci_3 alkoxy groups (e.g. methoxy, ethoxy, propoxy, etc.), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkyl groups (e.g. methyl, ethyl, propyl, etc.), and the aryl is optionally substituted with one or two of optional ones of them. As cycloalkyl groups of said optionally substituted cycloalkyl groups, mention is made of C3_7 cycloalkyl groups including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The kinds and number of the substituents of said optionally substituted cycloalkyl groups are substantially the same as those in the case of the above-mentioned aryl groups. As cycloalkenyl groups of said optionally substituted cycloalkenyl groups, mention is made of, among others, C3_6 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, eye1openteny1, cyclohexenyl, etc. The kinds and number of the substituents of said optionally substituted cycloalkenyl groups are substantially the same as those -10- in the case of the above-mentioned optionally substituted aryl groups. As heterocyclic groups of said optionally substituted heterocyclic groups, mention is made of, aromatic heterocyclic groups having, as the atoms (cyclic atoms) constituting the cyclic system, at least one hetero-atom selected from oxygen, sulfur and nitrogen, and saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups), preferably aromatic-heterocyclic groups. As said aromatic heterocyclic groups, mention is made of aromatic mono-cyclic heterocyclic groups (e.g. furyl, thienyl, pyrrolyl, oxazolyl, i.spxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, triazinyl, etc.) and aromatic condensed heterocyclic groups (e.g. benzofuranyl, isobenzofuranyl, benzo[b] thienyl, indolyl, isoindolyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoguinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, a-carbolinyl, /3-carbolinyl, y-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[l,2-b]pyridazinyl, pyrazolo[l,5-a]pyridyl, imidazo[1,2-a] pyridyl, imidazo[1,5-a]pyridyl, imidazo[l,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a. jpyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.), and, among them, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, etc. are preferable. Examples of said non-aromatic - 11 - heterocyclic groups include oxiranyl, azetidinyl, oxetanyl,.thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc. As substituents of 5 said optionally substituted heterocyclic groups, mention is made of alkyl groups (e.g. methyl, ethyl, propyl, etc.). Examples of substituents of said optionally substituted amino groups, optionally substituted hydroxyl groups and optionally substituted -10- thiol groups include lower (C^) alkyl (e.g. methyl, ethyl, propyl, etc.). And, when the hydrocarbon groups • in the optionally substituted hydrocarbon groups shown by Rpare alicyclic hydrocarbon groups or aryl group, they may have, as substituents, alkyl groups (e.g. 15 methyl, ethyl, propyl, etc.). Further, examples of Rj include optionally substituted Cj.g acyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, dimethylacetyl, trimethylacetyl, 20 etc. Said acyl group may have one to five appropriate substituents at any possible positions. Such substituents include halogen atoms (e.g. fluorine, chlorine, bromine). In the formulae (I), (I'), (I") and (I'"), as the 25 substituents of the "optionally substituted phenyl groups" shown by R2 or R2', mention is made of halogen (e.g. fluorine, chlorine, bromine, iodine), an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substitued 30 hydroxyl group, nitro, cyano, etc., and the phenyl group may be preferably substituted with 1 to 3 (preferably 1 to 2) of these substituents at any possible position. As the lower alkyl, mention is made of, for example, alkyl groups including 35 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., and especially methyl and 4 12 ethyl are preferable. As the lower alkoxy, mention is made of alkoxy groups including methoxy, ethoxy, n-propoxy, isopropoxy, n^-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc,, and especially methoxy and ethoxy are preferable. As substituents of said optionally substituted lower alkyl groups or optionally substituted lower alkoxy groups, mention is made of halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.), and one to five of these-may optionally--substituted at an optional possible position. As substituents at said optionally substituted hydroxyl group, mention is made of, for example, CX.A alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.), C3_6 cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aryl groups (e.g. phenyl, 1-naphthyl, 2-naphthyl, etc.), aralkyl groups (e.g. benzyl, phenethyl, etc.) These substituents may form a ring taken together with the adjacent substituents to each other, for example, such rings as shown by are mentioned. Said ring may be substituted with a lower (Cj_3) alkyl (e.g. methyl, ethyl, propyl, isopropyl, etc.) and the like. As aromatic heterocyclic groups of the "optionally substituted aromatic heterocyclic groups" shown by R2 or R2', mention is made of aromatic heterocyclic groups described in detail referring to Rlf and, among them, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc. are preferable. As substituents of said aromatic heterocyclic groups, mention is made of Ci_3 alkyl groups (e.g. methyl, 26 4 5 ethyl, propyl, etc.). In the formula (I") and as the alkyl groups of optionally substituted alkyl groups" shown by R2, mention is made of lower alkyl groups (e.g. 5 methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), and, among them, alkyl groups including methyl, ethyl, propyl, isopropyl, butyl and t-butyl are preferable.-■ As-the substit-uents— 10 of said optionally substituted alkyl groups, mention is made of halogen (e.g. fluorine, chlorine, bromine, iodine), lower alkoxy groups (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, etc.). Among the above-exemplified groups represented by 15 R2 or R2', optionally substituted phenyl groups, preferably substituted phenyl groups are preferable, with greater preference given to a phenyl group substituted with halogen, lower alkoxy, etc. In the above formulae (I), (I') and (I"), as the 20 "a substituent comprising an optionally esterified carboxyl group" shown by X', mention is made of optionally esterified carboxyl groups and a sxibstituent having an optionally esterified carboxyl group, etc. Said optionally esterified carboxyl groups are 25 substantially the same as those in the case of the below-mentioned optionally esterified carboxyl groups shown by Y. As the "a substituent comprising an optionally substituted carbamoyl group" shown by X', mention is 30 made of optionally substituted carbamoyl groups and a substituent having an optionally substituted carbamoyl group, etc. Said optionally substituted carbamoyl groups are substantially the same as those in the case of the below-mentioned optionally substituted carbamoyl 35 groups shown by Y. As the "a substituent comprising an optionally - 14 - substituted hydroxyl group" shown by X', mention is made of optionally substituted hydroxyl groups and a substituent having an optionally substituted hydroxyl group, etc. Said optionally substituted hydroxyl groups are substantially the same as those in the case of the below-mentioned optionally substituted hydroxyl groups shown by Y. As the "a substituent comprising an optionally substituted amino group" shown by X', mention is made of optionally substituted amino groups and a sxibstituent having an optionally substituted amino group, etc. Said optionally substituted amino groups are substantially the same as those in the case of the below-mentioned optionally substituted amino groups shown by Y. As the "substituent comprising an optionally substituted heterocyclic radical having a protonizable hydrogen "shown by X', mention is made of an optionally substituted heterocyclic radical having a protonizable hydrogen and a substituent having an optionally substituted heterocyclic radical having a protonizable hydrogen, etc. Said optionally substituted heterocyclic radicals are substantially the same as those in the case of the below-mentioned optionally substituted heterocyclic radicals shown by Y. Examples of X' include groups represented by the formula (a) X-Y wherein X is a bond or a divalent or trivalent atomic chain; Y is an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, an optionally substituted amino group or an optionally substituted heterocyclic radical having a protonizable hydrogen; the symbol is a single or double bond. In the formula (a), as the "divalent atomic chain" 26 4 5 - 15 - shown by X, mention is made ofr preferably, any one of divalent chains having 1 to 7 atoms, more preferably 1 to 4, constituting the straight-chain, and they may have side chains. 5 For example, mention is made of chains represented by the formula -(CHjJu-E- (CtDjp wherein m and n independently denote 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHC0-, -C0N(R5)- or 10 -NHCONH-; herein RA and R5 stands for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group; and R3 stands for H, a lower alkyl group, aralkyl group or acyl group. 15 As the alkyl groups of the "optionally substituted lower alkyl groups" shown by R4 and R5, mention is made of Ci.6 straight-chain or branched lower alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 20 etc.). As substituents of the said optionally substituted lower alkyl groups, mention is made of aromatic heterocyclic groups (e.g. furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), an optionally substituted amino 25 group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl groupf halogen atoms (e.g. fluorine, chlorine, bromine, iodine), etc. As substituents of said optionally substituted amino 30 group, optionally substituted hydroxyl group and optionally substituted thiol group, mention is made of a lower (C^)alkyl (e.g. methyl, ethyl, propyl, etc.), or the like. Examples of the said optionally esterified carboxyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, 1-naphthoxycarbonyl, etc., preferably methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl. As aralkyl groups of the "optionally substituted aralkyl groups" shown by and R5, mention is made of benzyl, naphthylmethyl,.phenylpropyl, phenylbutyl, etc. As substituents of said optionally substituted aralkyl groups, mention is made of halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkoxy groups (e.g. methoxy, ethoxy, propoxy group), hydroxyl group, amino group, carboxyl group, sulfhydryl group, etc. As substituents of the "optionally substituted phenyl groups" shown by RA and R5f mention is made of halogen atoms (e.g. fluorine, chlorine, bromine, iodine), Cj.3 alkoxy (e.g. methoxy, ethoxy, propoxy, etc.), Cj_3 alkyl (e.g. methyl, ethyl, propyl) etc. Provided that, R4 may be different in each chain. And, as the "lower alkyl groups" and "aralkyl groups" shown by R3, mention is made of lower alkyl groups (e.g. methyl, ethyl, propyl, butyl, tert-butyl, etc.), C7_15 aralkyl groups (e.g. benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, etc.). As the "acyl group" shown by R3, mention is made of lower alkanoyl groups (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), lower alkenoyl groups (e.g. acryloyl, methacryloyl, crotonoyl, isocrotonoyl, etc.), cycloalkanecarbonyl groups (e.g. cyclopropanecarbonyl group, cyclobutanecarbonyl group, cyclopentanecarbonyl group, cyclohexanecarbonyl group, etc.), lower alkanesulfonyl groups (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.), aroyl groups (e.g. benzoyl, p- 26451 * - 11 - toluoyl, 1-naphthoyl, 2-naphthoyl, etc.), aryl lower alkanoyl groups (e.g. phenylacetyl, phenylpropionyl, hydroatropoyl, phenylbutyryl, etc.), aryl lower alkenoyl groups (e.g. cynnamoyl, atropoyl, etc.), 5 arenesulfonyl groups (e.g.benzenesulfonyl/ p-toluenesulfonyl, etc.), etc. In additions, as X/ mention is made of a carbon chain containing a double bond or -L-C(OH)- (wherein L is a bond or a straight-chain or branched alkylene 10 chain). As said "carbon chain containing double bond", mention is made of, preferably, those in which the carbon number constituting the straight-chain portion ranges from 1 to 7, more preferably 1 to 4, and they may optionally have a side chain. While the double 15 bond at said carbon chain is contained in the straight-chain portion and/or branched chain portion, it is contained preferably in the straight-chain portion. Number of the double bond contained in said carbon chain is not restricted as far as possible, it ranges 20 preferably from 1 to 2. Examples of carbon chains containing said double bond include methine, vinylene, propenylene, butenylene, butadienylene, methylpropenylene, ethylpropenylene, propylpropenylene, methylbutenylene, 25 ethylbutenylene, propylbutenylene, methylbutadienylene, ethylbutadienylene, propylbutadienylene, pentenylene, hexenylene, heptenylene, hexadienylene and heptadienylene, preferably methine, vinylene, propenylene, butenylene and butadienylene. Herein, 30 when said carbon chain is trivalent, it binds to a carbon atom on Ring Ja, J2 or J' at any possible position by a double bond. Examples of the "straight-chain or branched alkylene chain" shown by L include straight-chain or 35 branched alkylene chain, more specifically, divalent ones such as methylene, ethylene, - 18 - trimethylene , tetramethylene, pentamethylene, hexamethylene, propylene, ethylmethylene, ethylethylene, propylethylene, butylethylene, methyltetramethylene and methyltrimethylene, and, preferably, Cx_3 ones such as methylene, ethylene, trimethylene and propylene. Among the above-exemplified groups shown by X', the groups represented by the formula (b) -Xx-Y wherein Xx is a bond or a divalent atomic chain; Y is an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, an optionally substituted amino group or an optionally substituted heterocyclic radical having a protonizable hydrogen, are preferable. In the formula (b), the "divalent atomic chains" shown by Xx are substantially the same as those in the case of the above-mentioned divalent atomic chains shown by X. In the formulae (a) and (b), as the "divalent atomic chain" sihown by X or Xx, more preferably, mention is made of straight-chain or branched alkylene chain, in which the carbon number constituting the straight-chain ranges from 1 to 7 (preferably from 1 to 4). Examples of said alkylene chain include divalent ones such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, propylene, ethyliriethylene, ethylethylene, propylethylene, butylethylene, methyltetramethylene and methyltrimethylene, and, preferably ones such as methylene, ethylene, trimethylene and propylene. In the formulae (a) and (b), as the "optionally esterified carboxyl groups" shown by Y, mention is made of lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, - 19 - 26 4 5 butoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, etc.), aryloxycarbonyl (e.g. phenoxycarbonyl, 1-naphthoxycarbonyl, benzyloxycarbony 1, etc.). Among them, carboxyl group, methoxycarbonyl and ethoxycarbonyl are preferable. Examples of substituents of the "optionally substituted carbamoyl group" shown by -Y. include, optionally substituted lower (Ci_6) alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), optionally substituted C3_6 cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally substituted aryl group (e.g. phenyl, 1-naphthyl, 2-naphthyl, etc.), optionally substituted aralkyl groups (e.g. benzyl, phenethyl, etc.), and, one or two of these substituents may independently substituted. As substituents at said optionally substituted lower (C^) alkyl and optionally substituted C3.6 cycloalkyl group, mention is made of, carboxyl group optionally esterified with a lower (C^s) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, isopentyl, neopentyl, etc.), aromatic heterocyclic groups (e.g. furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), amino group t hydroxyl group, phenyl group, etc., and, one to three of these substituents may independently substituted. As substituents of said optionally substituted aryl groups and optionally substituted aralkyl groups, mention is made off halogen atoms (e.g. fluorine, chlorine, bromine, iodine), carboxyl groups optionally esterified with a lower (Cx_ 4) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.). And, two substituents on a nitrogen atom may form a cyclic amino group taken together with 26 4 5 1 - 20 - ' 0 the nitrogen atom. Examples of such cyclic amino group include l-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, etc. Examples of substituents of the "optionally 5 substituted hydroxyl groups" shown by Y include lower (Ci.4) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.), C3_6 cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally substituted aryl groups (e.g. phenyl, 10 1-naphthyl, 2-naphthyl, etc.), optionally substituted aralkyl groups (e.g. benzyl, phenethyl, etc.), etc. As substituents of said optionally substituted aryl group and optionally substituted aralkyl group, mention is made of halogen atoms (e.g. fluorine, chlorine, 15 bromine, iodine), carboxyl groups optionally esterified with lower (C^) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.), etc. Examples of substituents of the "optionally substituted amino groups" shown by Y include lower (C^. 20 4) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.), C3_6 cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally substituted aryl groups (e.g. phenyl, 1-naphthyl, 2-naphthyl, etc.), optionally substituted 25 aralkyl groups (e.g. benzyl,, phenethyl, etc.), etc. As substituents of said optionally substituted aryl group and optionally substituted aralkyl group, mention is made of halogen atoms (e.g. fluorine, chlorine, bromine, iodine), carboxyl groups optionally esterified 30 with lower (C^) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.), etc. And, two substituents on a nitrogen atom may form a cyclic amino group taken together with the nitrogen atom. Examples of the cyclic amino group include l-azetidinyl, 1-35 pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, etc. - 21 - 26 4 5 i ^ : i > As heterocyclic radicals of the "optionally substituted heterocyclic radical having a protonizable hydrogen" shown by Y. mention is made of 5-7 membered (preferably 5 membered) monocyclic heterocyclic radical 5 containing at least one hetero atom selected from the group consisting of N, S and 0, more preferably N-containing heterocyclic radical. Especially, tetrazol-5-yl and groups represented by the formula /N i —K H 1 , wherein i stands for -0- or -S-; j stands for >C=0, 10 >C=S or >S02 (especially 2,5-dihydro-5-oxo-l,2,4- oxadiazol-3-yl, 2,5-dihydro-5-thioxo-l,2,4-oxadiazol-3-yl, 2,5-dihydro-5-oxo-l,2,4-thiadiazol-3-yl) are preferable. Said heterocyclic radical may be protected with an 15 optionally substituted lower alkyl (preferably CX.A alkyl), acyl, etc. As said optionally substituted lower alkyls, mention is made of methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc. Examples of said 20 acyl include lower (C2_5) alkanoyl, benzoyl, etc. Among the above-exemplified groups shown by X', an alkyl group substituted with an optionally esterified carboxyl group or an alkyl group substituted with an optionally substituted heterocyclic radical having a 25 protonizable hydrogen are preferable. In the formulae (I), (I'), (I") and (I'''), as aromatic heterocyclic rings shown by ring A, mention is made of aromatic heterocyclic groups described in detail referring to Rx. Among them, groups 30 represented by the formulae - 22 26 4 5 <?•'. $ «■ <?', & are preferable. As substituents of the "optionally substituted benzene rings" and "optionally substituted aromatic heterocyclic groups", mention is made of halogen (e.g. fluorine, chlorine, bromine, iodine), optionally substituted lower alkyl groups (e.g. methyl, ethyl, propyl, butyl, tert-butyl, etc.), optionally substituted lower alkoxy groups (methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.), nitro group, cyano, etc. the ring A may have 1 to 3 of these substituents, preferably 1 to 2. And, these substituents may form a ring, taken together with respectively adjacent substituents. As substituents of said optionally substituted lower alkyl groups or those of optionally substituted lower alkoxy groups, mention is made of halogen atoms (e.g. fluorine, chlorine, bromine, iodine), etc., which may have 1 to 3 substituents at optional positions. As rings A, those which are substituted with methoxy or chlorine atom are preferable, especially those substituted with chlorine are preferable. In the formula (I), as heterocyclic rings of the "7-membered heterocyclic ring containing at most three ring constituting hetero atoms" shown by ring Jlf mention is made of saturated or unsaturated 7-membered heterocyclic rings containing, as the atoms constituting the cyclic ring, at least one hetero-atom selected from 0, S(0)q (q is 0, 1 or 2) and N, provided that the number of hetero atoms in the atoms constituting the cyclic system (ring constituting - 23 - 264 5 atoms) of said heterocyclic ring is at most three. And, the ring may optionally have, besides the groups represented by R2, R2' and X', one or two appropriate substituents at any possible position. As 5 said substituent, when it binds to a nitrogen atom on the ring (Zx is N), mention is made of Cj.g straight-chain or branched alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc.), acyl groups such 10 as Cx_4 acyl groups (e.g. formyl, acetyl, propionyl, butyroyl, etc.), etc. Said alkyl or said acyl may have one to five of halogen atoms (e.g. fluorine, chlorine, bromine, iodine). And, when said substituent binds to a carbon atom or the ring Jlr mention is made of oxo, 15 thioxo, an optionally substituted hydroxyl group, an optionally substituted amino group, etc. Said optionally substituted hydroxyl group and said optionally substituted amino group are substantially the same as the "optionally substituted hydroxyl group 20 and the "optionally substituted amino group shown by Y. The ring is preferably substituted with oxo or thioxo, bt?s i.des the groups of Rx, R2' and X', at any possible position. D, as the atom constituting the cyclic ring (ring 25 constituting atom), is preferably C. And, K, as ring constituting atom, is preferably C. As the condensed ring composed of Ring A and Ring Jlr mention is made of 24 2 6 4 ~ 00 . O0 . orf OCT , QO . 0O . CO. The formula (I) is preferably one represented by the formula (I'). In the formula (I')/ as 7-membered heterocyclic rings shown by ring J2, mention is made of saturated 7-membered heterocyclic rings containing, as the atoms constituting the cyclic ring, at least one hetero atom selected from 0, S(0)q (q is 0, 1 or 2) and N. Z2, as ring constituting atom, is preferably S(0)q (q is 0, 1 or 2). K, as ring constituting atom, is preferably C. In the formula (I'), G is more preferably 0. In addition, as the formula (I'), one represented by the following formula wherein Rx, X', ring A, Z2 and G are substantially of the same meaning as above mentioned; Ring B is a substituted phenyl group, provided that, when Z2 is -0-and Ring A is an optionally substituted benzene ring, G is S, is preferable. Examples of substituents of the "substituted etc. -25 - *6451 „ [ 1 I phenyl group" shown by ring B are substantially the same as those in the case of the above mentioned . substituents of the "optionally substituted phenyl group" shown by R2' . 5 In the formula (I''), as heterocyclic rings of the "7- or 8-membered heterocyclic ring containing at most three ring constituting hetero atoms" shown by ring J', mention is made of saturated or unsaturated 7- or 8- membered heterocyclic rings containing, - as—the atoms 10 constituting the cyclic ring, at least one hetero-atom selected from 0, S(0)q (q is 0, 1 or 2) and N, provided that the number of hetero atoms in the atoms constituting the cyclic system (ring constituting atoms) of said heterocyclic ring is at most three. 15 And, the ring J' may optionally have, besides the groups represented by Rx, R2 and X', one or two appropriate substituents at any possible position. As said substituent, when it binds to a nitrogen atom on the ring J', mention is made of Cj_6 straight-chain or 20 branched alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc.), acyl groups such as acyl groups (e.g. formyl, acetyl, propionyl, butyroyl, etc.), etc. Said alkyl or said acyl may have one to 25 five of halogen atoms (e.g. fluorine, chlorine, bromine, iodine). And, when said substituent binds to a carbon atom or the ring J', mention is made of oxo, thioxO, an optionally substituted hydroxyl group, an optionally substituted amino group, etc. Said 30 optionally substituted hydroxyl group and said optionally substituted amino group are substantially the same as the "optionally substituted hydroxyl group and the "optionally substituted amino group shown by Y. The ring J' is preferably substituted with oxo or 35 thioxo, besides the groups of Ru R2 and X', at any possible position. - 26 - ! 6 4 % -■ * V,- As the condensed ring composed of Ring A and Ring J', mention is made of oO . oO . oO. ocy . O0_ . OO... .op. 0$. oO. 00 . g0. D, as ring constituting atom, is preferably C. The formula (I'') is preferably one represented by 5 the formula (I'''). Z3 is preferably S(0)q (q is 0, 1 or 2) . G is more preferably O. In the formulae (I' '' ), as alkyl groups shown by R7, mention is made of Cj_6 straight-chain or branched 10 lower alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc.), which may optionally be substituted with 1 to 5 halogen atoms (e.g. fluorine, chlorine, bromine, iodine). 15 As acyl groups shown by R7, mention is made of acyl groups (e.g. formyl, acetyl, propionyl, butyroyl, etc.), which may optionally be substituted with 1 to 5 halogen atoms (e.g. fluorine, chlorine, bromine, iodine)'. 20 The compounds of this invention are specifically disclosed as follows: 3,5-cis-7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester, 25 3,5-trans-7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2- $64 oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-propyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1 ,-2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-Chloro-5-(2-methoxyphenyl)-2-oxo-l-propyl-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-Chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo--l ,2,3,5-tetrahydro-4, l-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-Chloro-5-(2-methoxyphenyl)-l-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(2-chlorophenyl)-l-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(2-methoxyphenyl)-l-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid, (3R)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-l-isobutyl-2-oxo-lH-l,4-benzodiazepine-3-acetic acid methyl ester, (3R)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-l-isobutyl-2-oxo-lH,1,4-benzodiazepine-3-acetic acid, (3R, 5S) -7~Chloro-5- (2-chlorophenyl) -2,3,4,5-tetirahydro-l-isobutyl-2-oxo-lH-l,4-benzodiazepine-3-acetic acid, (3S)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-l- - 28 - 2 6 4 5 i isobutyl-2-oxo-lH-l,4-benzodiazepine-3-acetic acid methyl ester, (3S)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-l-isobutyl-2-oxo-lH-l,4-benzodiazepine-3-acetic acid, N-[3,5-trans-7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepin-3-acetyl]glycine methyl ester N-[3,5-trans-7-Chloro-5-{2-chlorophenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepin-3-acetyl]glycine, 3,5-trans-7-Chloro-5-(2-chlorophenyl)-3-dimethylaminocarbonylmethyl-l-neopc-ntyl-2-oxo-l ,2,3,5-tetrahydro-4,1-benzodiazepine, 7-Chloro-5-(2-chlorophenyl)-l-isobutyl-2-oxo-2,3,4,5-tetrahydro-lH-[l]-benzazepine-3-acetic acid ethyl ester, 7-Chloro-5-(2-chlorophenyl)-l-isobutyl-2-oxo-2,3,4,5-tetrahydro-lH-[1]-benzazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-thioxo-4,l-benzoxazepine-3-acetic acid ethyl ester, 3,5-trans-7-Cnloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-thioxo-4,l-benzoxazepine-3-acetic acid, 7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester, 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-thieno[2,3-e]oxazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester, 3,5-cis-7-Chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester, - 29 - 26 4 5 3 ,5-trans-7-Chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid, 3,5-cis-7-Chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo-5 1,2,3,5-tetrahydro-4,l-thieno[2,3-e]oxazepine-3-acetic acid, 3,5-trans-7-Chloro-l-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester, - - - — 10 3,5-cis-7-Chloro-l-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester, 3,5-trans-7-Chloro-l-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-15 acetic acid, 3,5-cis-7-Chloro-l-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl 20 2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl 2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid, 25 3,5-trans-7-Chloro-5-(2,3-dimethoxyphenyl)-1-isobutyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(2,4-dimethoxyphenyl)-1-isobutyl- 2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic 30 acid, 3,5-trans-7-Chloro-5-(3-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine 3-acetic acid, 3,5-trans-7-Chloro-5-(4-hydroxy-2-methoxyphenyl)-1-35 neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine 3-acetic acid, - 30 - ?645 3,5-trans-7-Chloro-5-(3-hydroxy-2-methoxyphenyl)-1-isobutyl-2-oxo-l ,2,3,5-tetrahydro-4, 1-benzothiazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(4-hydroxy-2-methoxyphenyl)-1-5 isobutyl-2-oxo-l ,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(3-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-l ,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, 10 3,5-trans-7-Chloro-5-(4-ethoxy-2-methoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceti.c acid, 3,5-trans-7-Chloro-5-(3-ethoxy-2-methoxyphenyl)-1-isobutyl-2-oxo-l ,2,3,5-tetrahydro-4,1-benzothiazepine-15 3-acetic acid, 3,5-trans-7-Chloro-5-(4-ethoxy-2-methoxyphenyl) -1-isobutyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(2-chloro-3-methoxyphenyl)-1-20 neopentyl-2-oxo-l ,2,3,5-tetrahydro-4,1-benzothiazepine 3-acetic acid, 3,5-trans-7-Chloro-5-(2-chloro-4-methoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine 3-acetic acid, 25 3,5-trans-7-Chloro-5-(2-chloro-3-methoxyphenyl)-1- isobutyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5-(2-chloro-4-methoxyphenyl)-1 -isobutyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-30 3-acetic acid, 3,5-trans-7-Chloro-5-(2-chloro-3-hydroxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine 3-acetic acid, 3,5-trans-7-Chloro-5-(2-chloro-4-hydroxyphenyl)-1-35 neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine 3-acetic acid, 31 264 5 1 6 3,5-trans-7-Chloro-5-(2-chloro-3-hydroxyphenyl)-1-isobutyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-Chloro-5-(2-chloro-4-hydroxyphenyl)-1-isobutyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, etc. As salts of the compound (I), (I1), (I") and (I'"), mention is made of, pharmaceutically acceptable ones, for example, inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate, etc.; metal salts such-as sodium salt, potassium salt, calcium salt, aluminum salt, etc., and salts with a base such as triethylamine salt, guanidine salt, dftmonixim salt, hydrazine salt, quinine salt, cinchonine salt, etc. The method of producing compounds of this invention is described as follows. A compound represented by the formula (la) CI a) wherein Y' stands for an optionally esterified carboxyl group among those defined by Y, and other symbols are of the same meaning as defined above, can be produced by the following methods. - 32 - 26 4 5 (Method A) H*. HSvr^C00B •Ba.g '0^E_Ei ■ A,),-C00B (JQ-CCHO.-COOE (II) 1 (TO B/ (la- 1) h B«-Q ^ ( kX Xcho.-coor, / (IF)*" Sj' (la-2) (Method B) ©^H (CHa)B—COOH 0Q-(CHi)«-COOE (II') ' oin * E ^ (la-3) K«-Q „ KCH2)B-COOR« Ri-Q _ (IV) (vT^ (la-4) 0Q-(CH,)B-COO8, . QQ- (CB,)„-COOH Sl (la-2) *' (la— 1) wherein R6 stands for the alkyl portion of the esterified carboxyl group defined by Y', Q stands for halogen, and other symbols are of the same meaning as - 33 - P p A f* " ^ ! 0 defined above].. Production of the formula (Ia-1) from the formula (II) in (Method A) and that of the formula (Ia-3) from the formula (II') in (Method B) can be conducted in a 5 solvent, for example, an ether-type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc., an alcohol type solvent such as methanol, ethanol, propanol, butanol, etc.; acetone, 10 dimethylformamide, dimethyl sulfoxide and acetic acid, and, when necessary, in the presence of an acid (hydrochloric acid, bromic acid, hydroiodic acid, su3furic acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid). Relative to one mole of the 15 compound represented by the formula (II) or (II'), the compound represented by the formula (III) is usually employed in an amount of 1 to 10 moles, preferably about 1 to 2 moles. The reaction temperature ranges from 0 to 200°C, preferably about 50 to 100°C. The 20 reaction time ranges usually from 1 to 24 hours, preferably about 1 to 3 hours. The method of producing the formula (Ia-2) from the formula (Ia-4) in (Method B) can be conducted in a solvent, for example, an ether type solvent such as 25 diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc., dimethylformamide or dimethyl, sulfoxide, and, depending on necessity, in the presence of a base (e.g. sodium hydride, lithium hydride, etc.). 30 Relative to one mole of the compound represented by the formula (Ia-4), a compound represented by the formula (V) is used, usually, in an amount ranging from 1 to 10 moles, preferably about 1 to 2 moles. The reaction temperature ranges from 0 to 200°C, preferably about 20 35 to 100°C. The reaction time ranges from 1 to 24 hours, preferable from about 1 to 5 hours. - 34 - 264 5 1 $ The method of producing the formula (la-2) from the formula (Ia-1) in (Method A) and that of producing (Ia-4) from the formula (Ia-3) in (Process B) can be conducted in a solvent, for example, water or an ether 5 type solvent such as diethyl ethfcr, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc., an alcohol type solvent such as methanol, ethanol, propanol, butanoXr—etc-acetone or-dimethyLformamide, and, 10 depending on necessity, in the presence of a base (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, barium hydroxide, etc.). Relative to one 15 mole of the compound represented by the formula (Ia-1) or the formula (Ia-3), a compound represented by the formula (IV) is employed, usually in an amount ranging from 1 to 10 moles, preferably from about 1 to 2 moles. The reaction temperature ranges from 0 to 100°C, 20 preferably from about 25 to 50°C. The reaction time ranges usually from 1 to 24 hours, preferably from about 3 to 10 hours. The method of producing the formula (Ia-1) from the formula (Ia-2) in (Method B) can be conducted in a 25 solvent, for example, water or an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane>- heptane, etc., an alcohol type solvent such as methanol, ethanol, propanol, butanol, etc., acetone or 30 dimethylformamide, and, depending on necessity, in the presence of a base (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, barium 35 hydroxide, etc.). The reaction temperature ranges from 0 to 100°C, preferably from about 20 to 50°C. The 264 5 - 35 - reaction time usually ranges from one to 24 hours, preferably about 3 to 10 hours. A compound represented by the formula (lb) ©ft 1/ (CE,),-r (Xb) wherein symbols are of the same meaning as defined above, can be produced by the following methods. (Method C) a* H (CH2)B-r */ (VI) (VII) <TX^CcHl)o-r •/ Clb— 1 > ® (VIII) (lb-2) C00H - 36 - 264 5 (Method D) it E t, p f?Y^o P-^Y^002 VTr0 A® ^SlH, (CBi),-r 1 ^Vc^CCH,),- am cm) * 1 h <ylir) —* " B (lb—3) Rs «/ !/ (lb— 1) (lb-2) wherein P stands for an amine-protecting group such as a carbobenzyloxy group, a t-butyloxycarbonyl group, etc., and other symbols are of the same meaning as defined above. In (Method C), (Method D), production of the formula (VIII) from the formula (VI) or of the formula (VIII') from the formula (VI') can be conducted in a solvent, for example, an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc., and a halogen type solvent such as dichloromethane, chloroform, etc., acetonitrile or dimethylformamide using a condensing agent such as diethyl cyanophosphonate, dicyclohexylcarbodiimide, etc., and, depending on necessity, in the presence of a base (e.g. triethylamine, 4-dimethylaminopyridine, N-methylpiperidine, etc.). Relative to one mole of a compound represented by the formula (VI) or the formula (VI'), a compound represented by the formula (VII) is employed usually in an amount ranging from 1 to 5 moles, preferably from about 1 to 1.5 mole. The - 37 - 26 4 5 i reaction temperature ranges from 0 to 100°C, preferably from about 20 to 50°C. The reaction time ranges from 1 to 24 hours, preferably from about 2 to 5 hours. In this case, the condensing agent is employed, relative 5 to one mole of the compound represented by the formula (VI) or the formula (VI'), in an amount usually ranging from 1 to 5 moles, preferably from about 1 to 2 moles. Production of the compound of the formula (Ib-1) from the compound of the formula (VIII) in (Method C) 10 or that of the compound of the formula (Ib-3) from the formu2a (VIII') in (Method D) can be conducted, for example, in an ether-type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, 15 etc., an alcohol type solvent such as methanol, ethanol, propanol, butanol, etc., acetone, dimethylformamide, acetonitrile solvent, a halogen type solvent such as dichloromethane, chloroform, etc., by a per se known method, for example, when P stands for a 20 carbobenzyloxy group, catalytic reduction using palladium, platinum or the like as the catalyst., while, P stands for a t-butoxycarbonyl group, by subjecting the compound obtained by removing the amine-protecting group P by dissolving or suspending the compound in an 25 acid (e.g, hydrochloric acid, bromic acid, trifluoroacetic acid) to catalytic reduction in, for example, an ether-type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, 30 etc;, an alcohol type solvent such as methanol, ethanol, propanol, butanol, etc., dimethylformamide, acetonitrile solvent, and, depending on necessity, in the presence of an acid (for example, hydrochloric acid, bromic acid, acetic acid, propionic acid, 35 methanesulfonic acid, toluenesulfonic acid, sulfuric acid, etc.). The reaction temperature ranges from 0 to - 38 - 2 6 4 5 f 100°C, preferably from about 30 to 70°C. The reaction time ranges usually from 1 to 24 hours, preferably from 3 to 10 hours. Production of the compound of the formula (Ib-1) from the formula (Ib-3) in (Method D) can be conducted substantially the same method for producing the compound of the formula (Ia-2) from the compound of (Ia-4) in (Method B) for the production of the compound represented by the formula (la) as described in the foregoing. And, production of the compound represented by the formula (Ib-2) from the compound represented by the formula (Ib-1) in (Method C), and, that of the compound of the formula (Ib-2) from the compound represented by the formula (Ib-1) in (Method D) can be conducted by substantially the same method as that for producing the compound represented by the formula (Ia-1) from the compound represented by the formula (Ia-2) in (Method B) for the production of the compound represented by the formula (la) described in the foregoing. A compound represented by the formula (Ic) 0Q-(cbo.-Y' (id t/ wherein symbols are of the same meaning as defined above, can be produced by th£ following methods. ) 264 - 39 - 5 ; I (IX) M (X) CO 0^ccE,)t-r !/ Q-(CBz)a-r (XI) R/ (CHO.-C00H (Ic- 1) (Ic— 2 ) wherein symbols are of the same meaning as defined above. 5 Production of the compound (X) from the compound (IX) obtained by a method substantially in accordance with the methods disclosed in J. Med. Chem., 27, 1508(1984), J. Med. Chem., 14, 851 (1971), can be conducted in substantially the same manner as in the 10 method of producing the compound represented by the formula (Ia-2) from the compound represented by the formula (Ia-4) in (Method B) for the production of the compound represented by the formula (la). Production of the compound represented by the formula (Ic-1) from 15 the compound represented by the formula (X) can be conducted, in a solvent, for example, an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc., 20 dimethylformamide or dimethyl sulfoxide, in the presence of sodium hydride, lithium hydride, lithium diisopropylamide, etc.. Relative to one mole of the compound represented by the formula (X), the compound represented by the formula (XI) is usually employed in 40 Z64 5 an amount ranging from 1 to 5 moles, preferably about 1 to 2 moles. The reaction temperature ranges from -78°C to 50°Cf preferably from -78°C to 0°C. The reaction time ranges usually from one to 24 hours, preferably about 3 to 10 hours. Production of the compound represented by the formula (Ic-2) from the compound represented by the formula (Ic-1) is conducted in substantially the same manner as in the production of the compound represented by,the formula (Ia-1)-from the compound represented by the formula (Ia-2) in (Method B). wherein symbols are of the same meaning as defined above can be produced by the following methods. - 41 - 264 5 [Method E] cxi') 00R8 CHaS0*C* (XIV) (Id— 4) - 42 - 264 5 j g [Method F] - 43 - 264 5 1 6 [Method G] CXXI) C Id—5) (I d— 3 ) 264 5 1 6 wherein each symbol is of t,he same meaning as defined above. Production of (XIII) from (VI'), (XV) from (XIV) 5 in the above (Method E), or that of (XVI) from (VI), (XVII) from (II) in (Method F) can be conducted by utilizing a per se known acylation reaction. The acylation can be conducted in a solvent, for example, an ether-type solvent...such as -diethyl ether, 10 tetrahydrofuran, dioxane, etc., a halogen type solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc., . dimethylformamide, dimethyl sulfoxide, etc., and, 15 depending of necessity, in the presence of water and a base (e.g. an organic base such as 4-dimethyl aminopyridine, triethylamine, triethylenediamine, tetramethyl ethylenediamine, etc., sodium hydrogencarbonate, potassium hydrogencarbonate, sodium 26 carbonate, potassium carbonate, sodium hydride, potassium hydride, etc.). Relative to one mole of the compound represented by the formula (VI'), (XIV), (VI) or (II), the amount of acid chloride or methanesulfonic chloride ranges usually from 1 to 10 moles, preferably 25 from about 1 to 3 moles. The reaction temperature ranges from'-50 to 100°C, preferably from about 0 to 50°C. The reaction time ranges usually from 1 to 48 hours,- preferably from about 5 to 10 hours. Production of (XIII') from (XIII) in the above-30 mentioned (Method E), that of (VI) from (VI') and that of (II) from (II.') in (Method F) can be conducted in a •solvent, for example, an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, 35 hexane, heptane, etc., an alcohol type solvent such as methanol, ethanol, propanol, etc., acetone, 264 5 7 dimethylformamide, etc. and, depending on necessity, in the presence of a base (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, 5 etc.). Relative to one mole of the compound represented by the formula (XIII), (VI') or (II'), the compound represented by the formula (V) is employed in an amount usually ranging from 1 to 10 moles, preferably from about 1 to 2 moles. The reaction 10 temperature ranges from 0 to 100°C, preferably from about 20 to 50°C. The reaction time ranges usually from 1 to 24 hours, preferably from about 3 to 10 hours. And, production of (Id-1) from (XV) in (Method E), 15 that of (II') from (VI') and reduction of the carbonyl group of (XVII) from (XVI) in (Method F) can be conducted by processing with a metal hydrogen complex (e.g. lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium 20 borohydride, etc.) in a protic solvent (methanol, ethanol, propanol, butanol, etc.) or an aprotic solvent (e.g. ethyl ether, tetrahydrofuran, dioxane, etc.). Relative to one mole of the compound represented by (XV), (VI') or (XVI), such a metal hydrogen complex is 25 employed in an amount ranging usually from 0.3 to 5 moles, preferably from 0.5 to 2 moles. The reaction temperature ranges from -20 to 100°C, preferably from about 20 to 50°C. Cyclization of (Id-2) from the formula (XVII) in 30 (Method F) is conducted in a solvent, for example, an ether-type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc., an alcoholic solvent such as methanol, ethanol, 35 propanol, butanol, etc., acetone, dimethylformamide, etc., and, depending on necessity, in the presence of a *64 5 1 $ base (e.g. sodium hydrogencarbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc.). Relative to one mole of the compound represented by the formula 5 (XVII), these bases are used usually in an amount ranging from one to 5 moles, preferably from about 1 to 2 moles. The reaction temperature ranges from -20 to 100°C. The reaction time usually ranges from 1 to 20 hours, preferably from..about 2 to 5 hours. . 10 The reaction to (XIV) from (XIII') in (Method E) can be conducted in alcohol represented by the formula (IV'), and, depending on necessity, in the presence of an inorganic acid such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, etc., or an 15 organic acid such as toluenesulfonic acid, methanesulfonic acid, etc. The reaction temperature ranges from -20 to 100°C, preferably from about 20 to 50°C. The reaction times ranges usually from 10 to 100 hours, preferably 10 to 48 hours. 20 Production of (Id-4) from (Id-1) in (Method E), and, that of (Id-4) from (Id-2) in (Method F) can be conducted in substantially the same manner as in the production of (Ia-1) from (Ia-2) in (Method B) in the synthesis of the compound represented by the formula 25 (la). Compounds represented by (Id-3) and (Id-5) in (Process G) can be produced in accordance with a per se known method. A compound represented by the formula (Id') 30 wherein symbols are of the same meaning as defined 47 264 5 1 e above, can be produced by subjecting a compound represented by the formula (Ik*) H20H ( Ik' ) / h wherein symbols are of the same meaning as defined above, to oxidation. As the solvent to be then employed, any one can be used so long as it does not hamper the reaction, which is exemplified by acetone, dioxane, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, etc., and as the oxidizing agent, use is made of permanganate, chromic acid, nickel peroxide, etc. Relative to one mole of the compound represented by the formula (Ik'), the oxidizing agent is employed in an amount ranging from 0.5 to 20 molar equivalents, preferably 1 to 3 molar equivalents. The reaction temperature ranges from 0 to 100°C, preferably from about 15 to 50°C. The reaction time ranges from 0.5 to 5 hours, preferably about 1 to 2 hours. Those represented by the formula (Ie) wherein symbols are of the same meaning as defined above, can be produced by the following method. (Ic) - 48 - 2645 j p R2 k*n 1 c=o rvC=s ^-Nin or ©cn„ fill,-Nil-(CII:),-V l,y . (XXIV) *" (VI) (XXII) 0q-(aiO„-r */ " */ 0 (XXIII) CIe-1) h a i )i-(CH,)-coon R/ N- -1 111 (Ie-2) wherein symbols are of the same meaning as defined above. The production of the compound of the formula 5 (XXXII) from the compound of the formula (VI) or the formula (XXII) can be conducted by using, relative to one mole of the compound represented by the formula (VI) or the formula (XXII), usually 1 to 10 moles, preferably 1 to 2 moles, of the compound represented by 10 the formula (XXIV) in, for example, an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc.; a hydrocarbon type solvent such as benzene, toluene, hexane or heptane; an alcohol type solvent such as methanol, ethanol, propanol, butanol, 15 etc.; or a solvent such as dimethylformamide, dimethyl sulfoxide, etc.. The reaction temperature ranges from 0 to 200°C, preferably from about 50 to 100°C. The reaction time ranges from 1 to 48 hours, preferably from about 10 to 24 hours. 20 The production of the compound of the formula (Ie) 26 4 5 1 from the compound of the formula (XXXII) can be conducted by using, relative to one mole of the compound represented by the formula (XXIII), usually 1-10 moles, preferably 1 to 2 moles of a carbonylation 5 agent including triphosgene, 1,1'-carbonyldiimidazole, 4-nitrophenyl, chloroformate or the like, in a solvent which does not hamper common reactions, for example, an ether type solvent such as diethyl ether, tetrahydrofuran or dioxane; a.hydrocarbon type solvent 10 such as benzene,, toluene, hexane or heptane; an alcohol type solvent such as methanol, ethanol, propanol or butanol; a solvent such, as dimethylformamide or dime-thyl sulfoxide. The reaction temperature ranges from 0 to 200°C, preferably from about 50 to 100°C. 15 The reaction time ranges from 0.5 to 24 hours, preferably from about 1 to 5 hours. The compound represented by the formula (If) Bz 0^-(CH2)ffi-Y< (If) */ wherein symbols are of the same meaning as defined above, can be produced by the following method: 26 4 I? iii 4-o + I 0 L (XXV) ©C; (XXVI) -©if;" NO a (XXVIII) axvii) jL ^(Tr^110 (XXIX) (XXXI) (XXXII) ra 0—c—cf3 Rs ^niii / ( A Kn ^— (Cllz)ni—COOH / - 51 - *645, wherein symbols are of the same meaning as defined above. Production of the compound represented by the formula (XXVII) from the compounds represented by the 5 formula (XXV) and the formula (XXVI) can be conducted by using, relative to one mole of the compound represented by the formula (XXV), 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents, of the compound represented by the formula.(XXVI), in an 10 ether type solvent such as dimethyl amide, ethyl ether, tetrahydrofuran, dioxane, etc., in the presence of sodium hydride, lithium hydride, alkyl lithium or the like-. The reaction temperature ranges from -78 to 100°C, preferably from about -20 to 30°C. The reaction 15 time ranges from 0.1 to 5 hours, preferably from about 0.5 to 2 hours. . Production of the compound represented by the formula (XXVIII) from the compound represented by the formula (XXVII) can be conducted by processing with a 20 metal hydrogen complex compound (for example, lithium aluminum hydride, sodium aluminum hydride, sodium borohydride, lithium borohydride, etc.) in a solvent, for example, a protic solvent (methanol, ethanol, propanol, butanol, etc.) or an aprotic solvent (e.g. 25 ethyl ether, tetrahydrofuran, dioxane, etc.). Such a metal hydrogen complex as above is usually employed, relative to one mole of the compound represented by the formula (XXVII), in an amount of 0.3 to 5 molar equivalents, preferably about 0.5 to 2 molar 30 equivalents. The reaction temperature ranges from -20 to 100°C, preferably from about 0 to 20°C. The reaction time ranges usually from 0.5 to 10 hours, preferably 1 to 5 hours. The compound represented by the formula (XXIX) can 35 be produced by subjecting the compound represented by the formula (XXVIII) to oxidation. Solvents then to be f - 52 - 264 5 employed may be any one so long as they do not hamper the reaction. For example, the compound can be produced by employing, for example, dimethyl sulfoxide and oxalyl chloride, or pyridine sulfur trioxide, in, 5 for example, a solvent such as dioxane, tetrahydrofuran, dichloromethane, dichloroethane, chloroform or the like. In this case, relative to one mole of the compound represented by the formula (XXVIII), an oxidizing agent is employed in an amount 10 of 0.5 to 20 molar equivalents, preferably 1 to 3 molar equivalents. The reaction time ranges from -78 to 50°C, preferably from -78 to 20°C. The reaction time ranges from 0.1 to 10 hours, preferably from about 0.2 to 2 hours. Depending on necessity, the reaction can 15 be conducted in the presence of a base (e.g. 4-dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, etc.). The compound represented by the formula (XXX) can be produced by subjecting the compound represented by 20 the formula (XXIX) and the compound represented by the formula (XXXV) to reductive amination. For example, relative to one mole of the compound represented by the formula (XXIX), 0.5 to 10 molar equivalents, preferably 0.5 to 1.5 molar equivalent of the compound represented 25 by the formula (XXXV) and 0.3 to 5 molar equivalents, preferably 0.5 to 1.5 molar equivalent of a metal hydrogen complex hydrogen (for example, sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride, etc.) are employed in an ether type 30 solvent such as diethyl ether, tetrahydrofuran, dioxane, etc.; a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc.; or an alcohol type solvent such as methanol, ethanol, propanol, etc.. The reaction temperature ranges from 0 to 100°C, 35 preferably from about 30 to 60°C. The reaction time ranges usually from one to 24 hours, preferably from 26*5I 6 about 3 to 10 hours. The compound represented by the formula (XXXI) can be produced by allowing the compound represented by the formula (XXX) to react with trifluoroacetic anhydride 5 or trifluoroacetyl chloride. This reaction can be conducted by using, relative to one mole of the compound represented by the formula (XXX), 0.5 to 3 molar equivalents, preferably 1 to 2 molar equivalents of trifluoroacetic anhydride or trifluoroacetyl 10 chloride, in an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc.; a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc.-;. a halogen type solvent such as dichloromethane, dichloroethane, chloroform, etc.; or dimethylformamide, 15 at temperatures ranging from 0 to 100°C, preferably from about 20 to 50°C, for about 5 minutes to 5 hours, preferably from about 0.1 to 1 hour. This production can be conducted, depending on necessity, in the presence of a base (e.g. an organic base such as 4-20 dimethyl aminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, etc. or sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc.). The compound represented by the formula (XXXII) 25 can be produced by subjecting the compound represented by the formula (XXXI) to catalytic hydrogenation using a palladium/carbon catalyst, in an alcohol type solvent such as methanol, ethanol, propanol, butanol, etc.; dimethylformamide, acetonitrile, acetic acid ethyl 30 ester, etc. The hydrogen pressure ranges from 1 to 100 atmospheric pressure, preferably 1- 10 atmospheric pressure, and the reaction temperature ranges from 0 to 200°C, preferably from about 20 to 50°C. The compound represented by the formula (XXXIII) 35 can be produced between the compound represented by the formula (XXXII) and a halogenated hydrocarbon group; or # 264 5 - 54 - reductive amination reaction between aldehyde or ketone group. Conditions for the production are those substantially the same as in the production of (Ia-2) from (Ia-4) in (Method B) in the case of production of 5 the compound represented by the afore-described formula (la) or those substantially the same as in the production of (XXX) from (XXIX) in the case of production of the compound represented by the formula (If). . . 10 Production of the compound represented by the formula (XXXIV) can be conducted by subjecting the compound represented by the formula (XXXIII) to hydrolysis in an alcohol type slvent such as methanol, ethanol, propanol, butanol, etc.; or an ether type 15 solvent such as tetrahydrofuran, dioxane, etc.? in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. The reaction temperature ranges from 0 to 100°C, preferably from 30 to 70°C, and the reaction time ranges from 1 to 48 hours, preferably 20 from about 10 to 20 hours. Production of the compound represented by the formula (If-1) from (XXXIV) can be conducted in substantially the same manner as in the method of producing (Ie-1) from (XXIII) in the case of producing 25 the compound represented by the formula (Ie). And, production of the compound represented by the formula (If-2) from (If-1) can be conducted by substantially the same procedure as in the case of producing (Ia-1) from (Ia-2) in (Method B) for production of the 30 compound represented by the formula (la). The compound represented by the formula (Ig) 264 5 1 r2 i-° ©^Vouco®. (ig) r/ wherein symbols are of the same meaning as defined above, can be produced by the method described below. /tv® rrvm 0 0 - \-ANHl ^Sh cit-ca,-ki 3 8i/ (invi) «m) « i, cxmn) cig-1) !\o p CIg-2) 5 wherein symbols are of the same meaning as defined above. The compound represented by the formula (XXXVI) can be produced in substantially the same manner as in the production of (Ia-2) from (Ia-4) in (Method B) in 10 the case of producing the compound represented by the formula (la), or by reductive amination which is substantially the same as in the production of (XXX) from (XXIX) in the case of producing the compound represented by the formula (If). - 56 - Production of the compound represented by the formula (XXXVII) can be conducted by allowing the compound represented by the formula (XXXVI) to react with malonyl dichloride in., for example, an ether type 5 solvent such as diethyl ether, tetrahydrofuran, dioxane, etc.; a halogen type solvent such as dichloromethane, chloroform, etc.; a solvent such as acetic acid ethyl ester, acetonitrile, water, etc. Relative to one mole af_the. compound (XXXVI), _malony]_. 10 dichloride is employed in an amount ranging from 1 to 10 molar equivalents, preferably from about 1 to 2 molar equivalents. The reaction temperature ranges from,-20 to 100°C, preferably from 0 to 70°C, and the reaction time ranges from 0.5 to 24 hours, preferably 15 from about 1 to 3 hours. The compound of the formula (Ig-1) can be produced by allowing the compound represented by the formula (XXXVII) to react with the compound represented by the formula (XXXVIII) in the presence of, for example, 20 sodium hydride, alkyl lithium, etc. For example, in a solvent such as dimethylformamide, acetonitrile, diethyl ether, tetrahydrofuran, dioxane, etc., relative to one mole of the compound represented by the formula (XXXVII), the compound represented by the formula 25 (XXXVIII) is employed in an amount ranging from 0.5 to 5 molar equivalents, preferably from 1 to 2 molar equivalents, and, sodium hydride or alkyl lithium is employed in an amount ranging from 0.5 to 3 molar equivalents, preferably from 1 to 1.5 molar 30 equivalents. The reaction temperature ranges from -20 to 100°C, preferably from 0 to 30°C, and the reaction time ranges from 0.5 to 24 hours, preferably from about 1 to 3 hours. The compound represented by the formula (Ih) 15 - 57 - 26 4 5 1 (Ih) wherein symbols are of the same meaning as defined above, can be produced by the following method. Si Ri — HOt (XXVIII) . (XXXIX) h gx E, (XXXX) Rt S Otb cH,)n-r - n—COOH 0 0 (Ih— 1) (Ih— 2 ) The compound represented by the formula (XXXIX) can be produced by subjecting the compound represented 5 by the formula (XXVIII) to hydrogenation in the presence of a palladium catalyst or hydrazine and Raney's nickel catalyst, etc. As the solvent, use is made of an alcohol type solvent such as methanol, ethanol, propanol, etc.; acetic acid ethyl ester, 10 tetrahydrofuran, dimethylformamide or acetonitrile. Production of compounds represented by the formulae (XXXX), (XXXXI), (Ih-1) and (Ih-2) can be conducted in substantially the same manner as in (Method G) for producing the compound represented by - 58 - 2645 the formula (Id). The compound represented by the formula (Ii) 1, 0^ni3_ccho»~ffl! (n) «/ wherein symbols are of the same meaning as defined above, can be produced by allowing a compound represented by the formula (Ij) I2 ©c!j3_(cbi) m—COOH (Ij) 8/ wherein symbols are of the same meaning as defined above, to react with diphenylphosphoryl azide in a 10 solvent in the presence of a base and then by treating the reaction product with an acid in a solvent. As the solvent to be employed for the reaction between the compound represented by the formula (Ij) and diphenylphosphoryl azide, any one can be used so long 15 as it does not hamper the reaction, and, mention is made of for example, a halogen type solvent such as dichloromethane, dichloroethane, chloroform, etc., an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., dimethylformamide, 20 among others. As the base to be employed, mention is made of triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylfenediamine, etc. Relative to one mole of the compound represented by the formula (Ij), diphenylphosphorylazide is used in an si amount ranging from 1 to 10 molar equivalents, preferably 1.5 to 3 molar equivalents. The reaction temperature ranges from -20 to 50°C/ preferably about 0 to 20°C. The reaction time ranges from 0.5 to 5 hours, 5 preferably about 1 to 2 hours. In the case of processing the reaction product obtained as above with acids, as the solvent to be employed, use is made of water, dioxane, dimethylformamide, etc., and, as the acid to be 10 employed, a mineral acid such as sulfuric acid, hydrochloric acid, nitric acid, hydrobromic acid, etc. The reaction temperature ranges from 20 to 200°C, preferably about 50 to 100°C. The reaction time ranges from 0.5 to 5 hours, preferably about 1 to 2 hours. 15 The compound represented by the formula (Ik) f (Ik) t/ wherein symbols are of the same meaning as defined above, can be produced by subjecting a compound represented by the formula (Im) 0c„j3_(cbi)»,-i-y' an° wherein m' denote 1, 2, or 3; other symbols are of the 20 same meaning as defined above, to reduction. For example, the compound (Ik) can be produced by processing the compound (Im) with a metal hydrogen complex compound (e.g. lithium aluminum hydride, sodium aluminum hydride, sodium borohydride, etc.) in a protic 25 solvent (method, ethanol, propanol, butanol, etc.) or - eo - 264 5 an aprotic solvent (e.g. ethyl ether, tetrahydrofuran, dioxane, etc.). The metal hydrogen complex compound is used, relative to one mole of the compound represented by the formula (Im), in an amount usually ranging from 5 0.3 to 5 molar equivalents, preferably about 0.5 to 2 molar equivalents. The reaction temperature ranges from -20 to 100°C, preferably from about 0 to 20°C. The reaction time ranges usually from 0.5 to 10 hours, preferably from about 1 to 3 hours. 10 And, the compound represented by the formula (Ik) can also be produced by converting the amine portion of the compound represented by the formula (Ii) into hydroxyl group. For example, the compound (Ik) can be produced by adding sodium nitrite to the compound (Ii) 15 in a solvent in the presence of an acid, then, by processing the azide compound thus obtained in a solvent in the presence of a base. For the preparation of the diazo compound, relative to one mole of the compound represented by the formula (Ii), sodium 20 nitrite is used in an amount ranging from 0.5 to 3 molar equivalents, preferably 1 to 1.5 molar equivalent in a solvent, for example, water, an aqueous dioxane or an aqueous dimethylformamide. As the acid to be employed, any one can be employed so long as it does 25 not hamper the reaction, for example, acetic acid, sulfuric acid, etc. in most cases. The reaction temperature ranges from -20 to 20°C, preferably from 0 to 5°C, and the reaction time ranges from 5 to 60 minutes, preferably from about 10 to 30 minutes. 30 A compound represented by the formula (XXXXII) !! cxxxxxi) 8/ 61 wherein Q' stands for halogen (chlorine, bromine, iodine), and other symbols are of the same meaning as defined above, which is an intermediate compound for synthesizing can be produced, in substantially the same manner as in the case of producing the compound represented by the formula (Ik) from the compound represented by the formula (Ii), by subjecting the compound represented by the formula (Ii) to diazotization with sodium-nitrite in hydrochloric acid, hydrobromic acid or hydroiodic acid, then by heating the resultant. The reaction temperature ranges from 20 to 200°C, preferably from 50 to 100°C. The reaction time-ranges from 5 minutes to 2 hours, preferably from about 15 to 30 minutes. A compound represented by the formula (In) wherein Y' ' stands for, among those defined by Y, esterified carboxyl group, an optionally substituted carbamoyl group, hydroxyl group, hydrogen, halogen (chlorine, bromine, iodine), other symbols are of the same meaning as defined above, can be produced by subjecting the compound represented by the formula (Ij) and a compound represented by the formula (XXXXIII) (In) NH-(CH)nr axxxni) wherein symbols are of the same meaning as defined above, to condensation. The compound represented by the formula (Ij) and the compound represented by the - 62 - 2 6 4 5 1 formula (XXXXIII) is condensed with a condensing agent in a solvent and, depending on necessity, in the presence of a base. The solvent to be employed is exemplified by a hydrocarbon type solvent such as 5 benzene, toluene, hexane, heptane, etc., a halogen type solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., an ether type solvent such as ethyl ether, tetrahydrofuran, dioxane, etc., acetonitrile, dimethylformamide, etc.. Examples 10 of the base include triethylamine, 4-• dimethylaminopyridine, triethylenediamine, tetramethyl ethylenediamine, etc. As the condensing agent, mention is made of that used in the field of peptide synthesis, as exemplified by dicyclohexylcarbodiimide, diethyl 15 cyanophosphonate, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide, etc. Relative to one mole of the compound represented by the formula (Ij), the compound represented by the formula (XXXXIII) is used in an amount of ranging from 0.5 to 2 molar 20 equivalents, preferably from 1 to 1.2 molar equivalent, and the condensing agent is used in an amount ranging from 0.5 to 5 molar equivalents, preferably from 1 to 2 molar equivalents. The reaction temperature ranges from 0 to 100°C, preferably 2 to 50°C. The reaction 25 time ranges from 0.5 to 24 hours, preferably from about 1 to 5 hours. A compound represented by the formula (Io) K2 I H 0 H R4 i n i i (^Aj[j^-(CH2)niN-C-N^(CH)nY'r (i0) / . B. 30 wherein symbols are of the same meaning as defined above, can be produced by allowing the compound represented by the formula (Ij) to react with - 63 - 2645 diphenylphosphoryl azide in a solvent in the presence of a base, then the reaction product is allowed to react with the compound represented by the formula (XXXXIII) in a solvent. The solvent in the reaction 5 between the compound represented by the formula (Ij) and diphenylphosphoryl azide is any one so long as it does not hamper the reaction, which is exemplified by a halogen type solvent such as dichloromethane, chloroform, dichloroethane, etc. and an ether type 10 solvent such as ether, tetrahydrofuran, dioxane, etc. or dimethylformamide. As the base to be employed, mention is made of triethylamine, 4- dime-thylaminopyridine, triethylenediamine, tetramethyl ethylenediamine. Relative to one mole of the compound 15 represented by the formula (Ij), diphenylphosphoryl azide is used in an amount ranging from 1 to 10 molar equivalents, preferably 1.5 to 3 molar equivalents. The reaction temperature ranges from -20 to 50°C, preferably from 0 to 20°C. The reaction time ranges 20 from 0.5 to 5 hours, preferably from about 1 to 2 hours. Examples of the solvent to be employed for the reaction between the reaction product thus obtained and the compound represented by the formula (XXXXIII) 25 include a halogen type solvent such as dichloromethane, dichloroethane, chloroform, etc., an ether type solvent such as ether, tetrahydrofuran, dioxane, etc., acetonitrile, dimethylformamide, etc. And-, depending on necessity, a base is employed. As the base, mention 30 is made of an organic base such as triethylamine, 4- dimethylaminopyridine, triethylenediamine, tetramethyl ethylenediamine, etc. Relative to one mole of the compound represented by the formula (Ij), the compound represented by the formula (XXXXIII) is used in an 35 amount ranging from 0.5 to 3 molar equivalents, preferably 1 to 1.5 molar equivalents. The reaction # 264 - 64 - temperature ranges from 0 to 150°C, preferably 30 to 100°C. The reaction time ranges from 0.5 to 24 hours, preferably about 1 to 3 hours. A compound represented by the formula (Ip) _.]L o r4 0QI^—(CH2)fflNH-C-(CE)n-Y' (Ip) / Ri wherein symbols are of the same meaning as defined above, can be produced by subjecting the compound represented by the formula (Ii) to condensation with a compound represented by the formula (XXXXIV) n ?4 (XXXXIV) H0C-(CH)nY* wherein symbols are of the same meaning as defined 10 above. This reaction can be conducted in entirely the same method of producing the compound represented by the formula (In). A compound represented by the formula (Iq) R (i,) / Hi wherein E' stands for oxygen atom or -NH- among the 15 groups defined above as E', and other symbols are of the same meaning as defined above, can be produced by respectively allowing the compound represented by the formula (Ii) and the compound represented by the formula (Ik) to react with a compound represented by # 26 4 5 - 65 - (XXXXV) q'-(&nr (xxxxv) wherein symbols are of the same meaning as defined above. More specifically, the compound represented by the formula (Ii) or the compound represented by the 5 formula (Ik) is allowed to react with the compound represented by the formula (XXXXV) in a solvent, for example, an alcoholic solvent such as methanol, ethanol, propanol, butanol, etc., an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., 10 dimethylformamide, etc. in the presence of a base, for example, an inorganic base such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc., an organic base such as triethylamine, 4-dimethylaminopyridine, 15 triethylenediamine, tetramethylethylenediamine, etc. sodium hydride, etc. Relative to one mole of the compound represented by the formula (Ii) or the formula (Ik), the compound represented by the formula (XXXXV) is used in an amount ranging from 0.5 to 1.5 molar 20 equivalent, and relative to one mole of the compound represented by the formula (Ii) or the compound represented by the formula (Ik), the base to be employed is used in an amount ranging from 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents. The 25 reaction temperature ranges from 0 to 200°C, preferably 20 to 100°C. The reaction time ranges from 0.5 to 24 hours, preferably from about 1 to 3 hours. A compound represented by the formula (Ir) - 66 - 26 4 5 S (7TlVcCH,).-S-ciB)„-r (Ir) if wherein symbols are of the same meaning as defined above, can be produced by allowing the compound represented by the formula (XXXXII) to react with a compound represented by the formula (XXXXVI) HS-a:H)nY* (xxxxvi) 5 wherein symbols are of the same meaning as defined above. Examples of the solvent to be employed include aprotic solvents including ethyl ether, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, etc., and, depending on necessity, 10 an inorganic base such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc., an organic base such as triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine, etc., 15 sodium hydride, cesium fluoride, etc. may be used. Relative to one mole of the compound represented by the formula (XXXXII), the compound represented by the formula (XXXXVI) is used in an amount ranging from 0.5 to 5 molar equivalents, preferably 1 to 2 molar 20 equivalents. The reaction temperature ranges from 0 to 200°C, preferably from 20 to 100°C. The reaction time ranges from 10 minutes to 5 hours, preferably about 30 minutes to 2 hours. A compound represented by the formula (Is) - 67 - *64 5 (CB,)I1-E-(C0)DCOOH (Is) wherein symbols are of the same meaning as defined above, can be produced by subjecting a compound represented by the formula (It) wherein Y''' stands for esterified carboxyl group among the groups defined above as Y, to hydrolysis. More specifically, the compound represented by the formula (It) is subjected to hydrolysis in a solvent such as • water, methanol, ethanol, propanol, butanol, etc., in the presence of an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.) or sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate or potassium carbonate, or in the presence of a mineral acid (e.g. nitric acid, hydrochloric acid, hydrobromic acid, folic acid, sulfuric acid, etc.) or trifluoroacetic acid at temperatures janging from 10 to 150°C, preferably 10 to 50°C. The reaction time ranges, varying with reaction temperatures, usually from 1 to. 24 hours, preferably about 2 to 10 hours. A compound represented by the formula (Iu) (It) / R. (Iu) I 264 5 wherein Y'''' stands for an optionally substituted carbamoyl group among the groups defined above as Y, and other symbols are of the same meaning as defined above, can be produced by subjecting a compound represented by the formula (Iv) i* -CODH (Iv) i wherein symbols are of the same meaning as defined above, to condensation with amine having the same substituent as that of "optionally substituted carbamoyl group" defined by Y''''. The reaction can be allowed to proceed under substantially the same conditions as in the case of producing the compound represented by the formula (In). A compound represented by the formula (Iw) Ra fflfrvx-o-R, v, ^ (Ii) / K( wherein R8 stands for a substituent of "an optionally substituted hydroxyl group" defined by Y, and other symbols are of the same meaning as defined above, can be produced, in substantially the same manner as the method of producing the compound represented by (Iq), from a compound represented by the formula (Ix) (Ix) 03~x_q' (x - 69 - 264 5 1 wherein symbols are of the same meaning as defined above, and a compound represented by the formula (XXXXVII), HO-R8, wherein the symbol is of the same meaning as defined above. A compound represented by the formula (Iy) wherein Rg stands for an optionally substituted amino group defined by Y, and other symbols are of the same meaning as defined above, can be produced, in substantially the same manner as producing the compound represented by the formula (Iq), from a compound represented by the formula (XXXXVIII), H-R9, wherein the symbol is of the same meaning as defined above, and the compound represented by the formula (Ix). A compound represented by the formula (Iz) wherein symbols are of the same meaning as defined above, can be produced by allowing a compound represented by the formula (la) (Iy) (Iz) (la) 70 2 6 4 5 , wherein symbols are of the same meaning as defined above, to react with metachloroperbenzoic acid in a solvent, for example, an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc., a halogen type solvent such as dichloromethar e., chloroform, etc., acetonitrile, dimethylformeuriide, etc. Relative to one mole of the compound (la)/ metachloroperbenzoic acid is used usually in an amount ranging from 1 to 5 moles, preferably about 1 to 1.5 mole. The reaction temperature ranges from 0 to 100°C preferably from 0 to 300O. The reaction time ranges from 1 to 10 hours, preferably from about 1 to 2 hours. A compound represented by the formula (l£) wherein symbols are of the same meaning as defined above, can be produced by employing the compound of the formula (Iz) or the formula (la) as the starting material, in substantially the same manner as in the case of producing the compound of the formula (Iz) from the compound of the formula (la). r2 (I £) / h - 71 - 264 5 A compound represented by the formula (Iy). Rz n X' (1 (1 7) wherein symbols are of the same meaning as defined above, can be produced by subjecting a compound wherein symbols are of the same meaning as defined above, to reduction in a solvent, for example, water, an alcoholic solvent such as methanol, ethanol, propanol, etc., an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc., a halogen type solvent such as dichloromethane, chloroform, etc., employing, as a reducing agent,sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride, etc. Relative to one mole of the compound represented by the formula (16), the reducing agent is employed in an amount ranging from 0.2 to 5 molar equivalents, preferably from about 0.3 to 1 molar equivalent. The reaction temperature ranges from 0 to 100°C, preferably from 20 to 50°C. The reaction time ranges from 0.5 to 10 hours, preferably from about 1 to 3 hours. represented by the formula (15) ?2 i=R (I 5) / - 72 - 26 4 5 1 A compound represented by the formula (10) • (10) wherein symbols are of the same meaning as defined above, can be produced by allowing a compound represented by the formula (Itc) wherein symbols are of the same meaning as defined above, to react with a Lawesson's reagent or phosphorus pentasulfide in a solvent, for example, an alcoholic solvent such as methanol, ethanol, propanol, etc., an ether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc., a hydrocarbon type solvent such as benzene, toluene, hexane, heptane, etc., halogen type solvent such as dichloromethane, chloroform, etc., hexamethylphosphoramide, dimethyl sulfoxide, etc. Relative to one mole of the compound of the formula (Itt), the Lawsson's reagent or phosphorus pentasulfide is used in an amount ranging from 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents. The reaction temperature ranges from 0 to 150°C, preferably from about 50 to 100°C . The reaction time ranges from one to 24 hours, preferably from about 3 to 10 hours, cijt) I \ - 73 - 264 5 A compound represented by the formula (IX) cia) wherein symbols are of the same meaning as defined above, can be produced by allowing a compound represented by the formula (Iy) to react with a compound represented by the formula (XXXXIX), R7-Q', wherein symbols are of the same meaning as defined above, in substantially the same conditions as in the cases of producing (XIII) of (Method E), (VI), (II) in (Method F) in the compounds represented by the formula (Id). While the compounds represented by the general formula (I), (I'), (I'') and (I''') of this invention have a squalene synthetase inhibiting action or an antifungal action, among the compounds used in the present invention, there are compounds capable of inhibiting other enzymes in the pathway of cholesterol biosynthesis. Be the matter as it may, the compounds represented by the formula (I), (I'), (I'') and (I'") inhibit biosynthesis of cholesterol, which is useful for the prophylaxis or therapy of hypercholesterolemia or coronary sclerosis of mammals (e.g. mouse, rat, rabbit, dog, cat, cow, pig and human being), and also useful for the prophylaxis or therapy of fungal infection. These compounds can be administered to man orally or non-orally. The orally administrable compositions may be in a solid or liquid form, more specifically - 74 - 264 5 tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsule), syrups, emulsions, suspensions or the like. These compositions can be prepared by a per se 5 known method and contain carriers or excipients conventionally used in the field of pharmaceutical preparation, for example, carriers or excipients such as lactose, starch, sucrose or magnesium stearate for preparing tablets. • . 10 The non-orally administrable compositions are exemplified by injections and suppositories, and the injections include hypodermic injections, intradermal injections and intramuscular injections. These injections can be prepared by a per se known method, 15 more specifically, by suspending or emulsifying the compound of this invention in a sterile water or oil conventionally used for preparing injectable compositions. The aqueous liquid Lo be used for preparation of injections include physiological saline 20 solution and isotonic solution, and, depending on necessity, a suitable suspending agent such as sodium carboxymethyl cellulose, a non-ionic surfactant or the like may be jointly used. As the oil, mention is made of sesame oil, soybean oil, etc., and benzyl benzoate, 25 benzyl alcohol etc. as a solubilizer may be jointly used. Injections thus prepared are, in general, filled in appropriate ampoules. The compounds (I), (I'), (I'') and (I''') or salts thereof are low in toxicity and can be used safely. 30 While the daily dosage varies with the conditions or body weight of the subject patient, kinds of the compounds, administration route, etc., in the case of administering the compound of the present invention for the therapy of hypercholesteremia, a daily oral dosage 35 per adult human is about 1 to 500 mg, preferably about 10 to 200 mg. Within this range, no toxicity is 26 4 5 1 6 observed at all. Effective daily dose per adult human of the compounds (I), (I'), (I'') and (!'''), when administered to mammals (e.g. man) as a squalene synthetase inhibitor, ranges from 5 about 1 to 500 mg, preferably from about 10 to 200 rag in the case of oral administration, while, in the case of non-oral administration (e.g. injection, suppository), ranges from about 0.1 to 100 mg, preferably from about 1 to 50 mg. 10 Further, the compounds (I), (I')/ (!'') and (I''') show a broad anti-bacterial activities as determined by the broth or agar dilution method. Effective daily dose per adult human of the compounds (I), (I1), (I'') and {!''') for the antifungal purpose to be 15 administered to mammals (e.g. man, etc.) ranges from about 0.1 to 100 mg, preferably from about 1 to 50 mg in the case of oral administration, while in the case of non-oral administration (e.g. injection, suppository, etc.) it ranges from about 0.1 to 100 mg, 20 preferably from 1 to 50 mg. In the present specification, when amino acids, etc. are shown by abbreviations, they are based on those in IUPAC-IUB Commission on Biochemical Nomenclature or on those commonly used in the field 25 concerned. For example, Trp: tryptophane, Ser: serine, Asp: aspartic acid, Glut glutamic acid, Gly: glycine, Leu: Leucine, Ala: alanine, Me: methyl, Et: ethyl, and Ph: phenyl. And, when the amino acid has optical isomers, they are L-isomers, unless otherwise 30 specified. - 76 - 264 5 1 6 [Examples] The following examples, formulation examples and test examples are intended to illustrate the present invention in further detail and should by no means be construed as defining the metes and bounds of the invention. In the following description, stereoisomers are obtained depending of the kinds of compounds, when the groups X' and R2 or R2' bind to saturated carbon atoms. An isomer in which the groups X' and R2 or R2' are oriented in the same direction relative to the face of Ring J2 or J' is named cis-isomer, while another in which the groups X' and R2 or R2' are oriented in the adverse directions to each other is named trans-isomer. Example 1 3,5-Trans-7-chloro-5-(2-chlorophenyl)-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester 2-Amino-5-chloro-o6-(2-chlorophenyl)benzylalcohol (6 g) and thiomalic acid (3.42 g) were dissolved in a mixture of conc. hydrochloric acid (60 ml) and acetic acid (60 ml), and the solution was stirred for 3 hours at 100°C. The reaction mixture was cooled, to which was added 100 ml of 3N aqueous solution of sodium hydroxide. The mixture was extracted with dichloromethane containing tetrahydrofuran by 10% (V/V). The extract solution was washed with a saturated aqueous solution of ammonium CI B CI ^COOCH* - 77 - 264 5 1 chloride, which was then dried over anhydrous sodium sulfate. The solvent was distilled off, and the dimethylformamide by 3%(V/V), and the solution was heated overnight under reflux. The solvent was distilled off. To the residue were added methanol (50 ml) and conc. sulfuric acid (0.5 ml). The mixture was heated for 3 hours under reflux. The solvent was distilled off. The residue was dissolved in dichloromethane, and the solution was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated aqueous saline solution, which was then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixture solvent of dichloromethane/petroleum ether to give 5.6 g of colorless crystals, m.p.200-205°C. Elemental Analysis for C18Hi5Cl2N03S. 0. 3H20: Calcd.: C 53.82; H 3.91; N, 3.49 Found : C 53.78; H 4.04; N, 3.22 Example 2 3,5-cis-7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester 5-Chloro-a-(2-chlorophenyl)-2-(neopentylamino)benzyla-lcohol (6.5 g) and thiomalic acid (2.85 g) were processed in substantially the same manner as in Example 1. The residue then obtained was residue was dissolved in xylene containing fcCvJ - 78 - 264 5 1 recrystallized from a mixture solvent of dichloromethane/petroleum ether to give 2.31 g of colorless crystals, m.p.153-156°C. Elemental Analysis for C^HjsCIjNOsS : 5 Calcd.: C, 59.23; H, 5.40; N, 3.00; S, 6.87 Found : C, 58.99; H, 5.32; N, 2.76; S, 6.80 Example 3 3,5-trans-7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic 10 acid methyl ester The residue obtained by concentration of the mother liquor resulting from the elimination of the cis-isomer by filtration in recrystallization in Example 2 was dissolved in methanol (30 ml). To the solution was 15 added potassium carbonate (0.87 g), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated, which was dissolved in dichloromethane. The solution was washed with water, then dried over anhydrous sodium sulfate. The solvent 20 was distilled off, and the residue was purified by means of a silica gel column chromatography (hexane: acetic acid ethyl ester = 3:1 (V/V) as an eluent) to give a solid product, which was recrystallized from dichloromethane/petroleum ether to give 2.73 g of 25 colorless crystals, m.p.133-136°C. Elemental Analysis for C23H25Cl2N03S: Calcd.: C, 59.23; H, 5.40; N, 3.00; S, 6.87 Found : C, 59.36; H, 5.30; N, 2.84? S, 6.86 ^ -79- 26 4 5 1 6 Example 4 3,5-trans-7-Chloro-5-(2-chlorophenyl)-l-propyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester m O-C] Cfi, 5 A solution of 3,5-trans-7-chloro-5-(2- chlorophenyl)-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (0.5 g) obtained in Example 1 in dimethylformamide (5 ml) was cooled to 0 °C. To the solution was added sodium 10 hydride (36 mg), and the mixture was stirred for 5 minutes at 0°C. To this solution was added 1-bromopropane (0.19 g), and the mixture was stirred for 3 hours at room temperature. To the reaction mixture was added water, which was extracted with 15 dichloromethane. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was purified by means of a silica gel 20 column chromatography (hexane:acetic acid ethyl ester = 3:1 (V/V) as an eluent) to give 0.56 g of a colorless oily compound. IR v,^(neat)cm"1: 1740, 1670. 1H-NMR(CDC13) 6: 0.978(3H,t,J=7.6Hz), 1.563-25 1.881(2H,m), 2.445(lH,dd,J=4.0, 17.0Hz), 3.170(lH,dd,J=10.6, 17.0Hz), 3.477(lH,ddd,J=5.2, 10.2, 13.6Hz), 3.673(3H,s), 3.720(lH,dd,J=4.0, 10.6Hz), 4.215(lH,ddd,J=6.0, 10.4, 13.6Hz), 6.023(lH,s), 6.633(lH,d,J=2.2Hz), 7.214-7.477, 7.766-7.798(6H,m) 30 Example 5 - so - ^ 6 4 j j g By substantially the same manner as in Example 4, the following compounds were obtained. [Table 1] Cpd. No. R nu p# CC) Molecular Formula Elemental Analysis (Experimental values) C H N 1 CHa 183-185 C|«lirCltNOaS 55.62 4. 18 3.41 (55.40 4. 04 3.47) 2 . CHJCHJ 142-143 CJOHI»CliN0jS 56.61 4.51 3.30 (56.55 4.50 3.39) 3 CH2CH(CHJ)» 157.5-158.5 C22H1JCIJNOJS 58.41 5.12 3.10 (58.60 5.21 3.16) 264516 Example 6 7-Chloro-5- (2-methoxyphenyl) -2-oxo-l ,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester OOCHj 2 -Amino-5 -chloro-a- (2-methoxyphenyl) benzyl alcohol (lg) and thiomalic acid (0.60 g) were allowed to ptoceed in substantially the same manner as in Example 1 to give 1.34 g of a pale yellow amorphous solid. IR v ^ (KBr) cm"1: 1740, 1680. 1H-NMR (CDC13) 6: 2.394-2.535(lH,m), 3.031-3;187(lH,m), 3.674, 3.691(6H,each s), 3.792-3.925(lH,m), 5.512, 6.237(IH,), 6.744-7.783(7H,m) Example 7 3,5-trams-7-Chloro-5-(2-methoxyphenyl)-2-oxo-l-propyl-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester ^COOCHi 7-Chloro-5-(2-methoxyphenyl)-2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester (0.5 g) obtained in Example 6 was allowed to proceed in substantially the same manner as in Example 4 to give 0.17 g of colorless crystals, m.p.81-107°C. Elemental Analysis for C^H^CINO^S. 0 . 3H20: Calcd.: C, 60.14; H, 5.64; N, 3.19 264 5 1 Founds C, 59.97; H, 5.81; N, 3.01 Example 8 5-Chloro-a-(2-methoxyphenyl)-2-(neopentylami.no )benzylalcohol or 2-isobutylamino-5-chloro-a-(2-methoxyphenyl)benzyl alcohol was allowed to proceed substantially the same manner as in Examples 2 and 3 to give the following compounds. [Table 2] cpd. No. r-r~ R n. p. TO Molecular Formula Elemental Analysis (Experimental values) C H N 1 CHjCH(CHs)z 178-179 C2JH2BC1N04S 61.67 5.85 3.13 (61.48 5.81 3.06) 2 CH2C(CHs)s 208-211 C24B28CINO4S 62.39 6.11 3.03 (62.13 6.15 2.99) Example 9 3,5-trans-7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid 264 5 1 - 83 - O-Cl fcoj HjCr^CHi To a mixture of water (2 ml) and methanol (4 ml) were added 3,5-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-5 3-acetic acid methyl ester (0.15 g) obtained in Example 3 and potassium carbonate (0.07 g). The mixture was heated at 60°C for 2 hours under reflux, to which was added water (50 ml). The solution was made acid with IN HC1, which was extracted with dichloromethane. The 10 extract solution was washed with a saturated aqueous solution of ammonium chloride, which was dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was recrystallized from dichloromethane/petroleum ether to give 0.12 g of 15 colorless crystals, m.p.269-271°C Elemental Analysis for C22H23C12N03S: Calcd.: C, 58.41; H, 5.12; N, 3.10; S, 7.09 Found : C, 58.39; H, 5.19; N, 2.84; S. 6.78 Example 10 20 In substantially the same manner as in Example 9, the following compounds were synthesized. - 84 - 264 5 1 6 [Table 3] Q-x cl,oq / cpd. No. R X o. p. CC) lolecular Fornula Eleaental Analysis (Experinental values) C H N - 1 H 01 270-283 (decobp.) CITHis&INOJS 53.41 3.43 3.66 (53.08 3.71 3.38) 2 (CBi)jCHs CI 237-241 CnHi sCljNOiS 56.61 4.51 3.30 (56.34 4. 63 3.13) 3 CHj CI 183-185 Ct.HuCliNOjS 55.62 4.18 3.41 (55.40 4.04 3.47) 4 CHJCHJ CI 236-239 Ct ill7CI1NO3S •0.3H»0 54.89 4.27 3.37 (54.93 4.20 3.41) 5 CHtCH(CB3)i CI 225-228 CtifljjCliNOjS '0.3H20 56.84 4.91 3.16 (56.86 5.08 3.06) 6 (CH^CBa OCBs 206-208 C2,1,zC1N04S 60.07 5.28 3.34 (60.10 5. 17 3.38) 7 CHjCH(CB3), OCBj 247-248 Cdecomp.) CnH^ClNO.S •0.2HsO 60.39 5. 62 3.20 (60.31 5.60 2.95) 8 CB,C(CH3)s OCBj 270-285 Cdecomp.) CtjHstClNOiS 61.67 5.85 3.13 (61.33 5.92 2.97) 264 5 1 6 Example 11 (3R)-7-Chloro-5-(2-chlorophenyl) - 2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-3-acetic acid methyl ester q-cl H 5 (1) (3R)-3-Benzyloxycarbonylamino-3-[N-[4-chloro-2-(2-chlorobenzoyl)phenyl]carbamoyl]propionic acid methyl ester In dichloromethane (50 ml) was dissolved N-benzyloxycarbonyl-D-aspartic acid beta-methyl ester 10 (4.3 g). The solution was cooled to 0°C, to which were added N-methylmorpholine (1.6 g) and isobutyl chloroformate (2.2 g). The mixture was stirred for 10 minutes at room temperature, to which was added a solution of 2-amino-2',5-dichlorobenzophenone (4.1 g) 15 in dichloromethane (20 ml). The mixture was heated for 20 minutes under reflux. The reaction mixture was stirred for two days at room temperature, to which was then added dichloromethane (100 ml). The mixture was washed with a 10% aqueous solution of citric acid, a 20 saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was recrystallized from hexane/ethyl acetate (3:1 (V/V) to give 3.73 g of 25 pale yellow crystals, m.p.160-162°C. (2) (3R)-7-Chloro~5-(2-chlorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid methyl ester To a solution of the compound obtained in (1) (3.76 g) in methanol (60 ml) were added 10% 'Pd/C (0.5 30 g) and conc. HC1 (0.59 ml). The mixture was subjected - 86 - 264 5 1 6 to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was removed and the solvent was distilled off. The residue was dissolved in mixture solvent 5 (dichloromethane;tetrahydrofuran=9:1) (100 ml). The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off, and the 10 residue was dissolved in dimethylformamide (20 ml), to which was added acetic acid (1 ml), followed by stirring for two hours at 60°C. To the reaction mixture was added ethyl acetate (50 ml), which was stirred for two hours at 60°C. To the reaction mixture 15 was added ethyl acetate (50 ml), which was washed with a 5% aqueous solution of potassium hydrogensulfate, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution. Then the solvent was distilled off, and the residue was 20 recrystallized from ethyl ether to give 2.97 g of colorless crystals, m.p.168-170°C. Elemental Analysis for C18H1AC12N203. 0 .75H20: Calcd.: C, 55.33; H, 4.00; N, 7.17 Found : C, 54.92; H, 3.60; N, 7.21 25 Example 12 (3R)-l-Isobutyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-3-acetic acid methyl ester I 264516 - 87 - (3R)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH,1,4-benzodiazepine-3-acetic acid methyl ester (0.5 g) obtained in Example 11 and isobutyl bromide (0.23 g) were allowed to proceed in 5 substantially the same manner as in Example 4 to give 0.3 g of a colorless oily compound. IR (neat) cm"1: 1740, 1680, 1600-^-NMRfCDCla) S: 0 . 795 ( 3H,d, J=6 . 4Hz ) , 0.882(3H,d,J=6.6Hz), 1.759(lH,m), 3.220(lH,dd,J=7.0, 10 16.8Hz), 3.438(lH,dd,J=7.4, 16.8Hz), 3.528(lH,qd,J=4.8, 14.2Hz), 3.723(3H,s), 4.167(IH,t,J=7.1Hz ) , 4.332(lH,dd,J=10.0, 14.2Hz), 7.078(lH,d,J=2.4Hz), 7 . 37-1-7 .532 (6H,m) Example 13 15 (3R)-l-Isobutyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-3-acetic acid (3R)-l-Isobutyl-7-chloro-5-(2-chlorophenyl)- 2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-3-acetic acid 20 methyl ester (0.23 g) obtained in Example 12 was allowed to proceed in substantially the same manner as in Example 9 to give 0.11 g of colorless crystals, m.p.l75-178°C. Elemental Analysis for C21H20CI2N2O3.0 . 2H2: 25 Calcd.: C, 59.65; H, 4.86; N, 6.62 Found : C, 59.65; H, 4.96; N, 6.62 Example 14 (3R,5S)-l-Isobutyl-7-chloro-5-(2-chlorophenyl)-2,3,4,5-tetrahydro-2-oxo-lH-l,4-benzodiazepine-3-acetic acid « - 88 - 2645 In a mixture solvent (methanol:water=6:1) (0.7 ml) was dissolved (3R)-l-isobutyl-7-chloro-5-(2-chlorophenyl )-2,3-dihydro-2-oxo-lH-l, 4-benzodiazepine-3-acetic acid (30 mg) obtained in Example 13. To the solution was 5 added sodium borohydride (10 mg). The reaction mixture was stirred for two hours at room temperature, to which were added dichloromethane (50 ml) and water (50 ml). The aqueous layer was made acid, then the organic layer was washed with a saturated aqueous 10 saline solution, followed by drying over anhydrous sodium sulfate. The solvent was removed, and the residue was recrystallized from dichloromethane/petroleum ether to give 17 mg of colorless crystals, m.p.184-188°C. 15 Elemental Analysis for C21H22CI2N2O3 .H20: Calcd.: C, 57.41; H, 5.50; N, 6.38 Found : C, 57.56; H, 5.16; N, 6.40 Example.15 (3S)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH-20 1,4-benzodiazepine-3-acetic acid methyl ester o-ci H - 89 - 264 5 1 6 N-Benzyloxycarbonyl-L-aspartic acid beta-methyl ester was allowed to proceed in substantially the same manner as in Example 11 to give a non-crystalline solid product. IR (KBr)cm"1 s 1740, 1690, 1610. 1H-NMR (CDC13) 6: 3.218(lH,dd,J=6.8, 17.0Hz), 3.447(lH,dd,J=7.4, 17.0Hz), 3.756(3H,s), 4.234(1H,t,J=7.1Hz), 7.069-7.130, 7.353-7.486(7H,m) Example 16 (3S)-l-Isobutyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH,l,4-benzodiazepine-3-acetic acid methyl ester (3S)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-3-acetic acid methyl ester obtained in Example 15 was allowed to proceed in substantially the same manner as in Example 4 to give a pale yellow oily compound. IR vaax(neat) cm"1: 1740, 1680, 1610. ^-NMR (CDCI3) 6: 0 . 794 (3H,d, J=6 .6Hz), 0.881(3H,d,J=6.8Hz), 1.728(lH,m), 3.219(lH,dd,J=7.0, 16.8Hz), 3.437(lH,dd,J=7.4, 16.8Hz), 3.528(lH,qd,J=4.4, 14.2Hz), 3.723(3H,s), 4.166(IH,t,J=7.1Hz), 4.332(lH,dd,J=10.0, 14.2Hz), 7.077(lH,d,J=2.4Hz), 7.370-7.530(6H,m) Example 17 (3S)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-l-isobutyl-2-oxo-lH-l,4-benzodiazepine-3-acetic acid CH, - 90 - 26 4 516 ""y^cooh CHs (3S)-l-Isobutyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-3-acetic acid methyl ester was allowed to proceed substantially in the same manner as in Example 9 to give a colorless solid compound, m.p.171-179°C Elemental Analysis for C21H20CI2N2O3: Calcd.: C, 60.15; H, 4.81; N, 6.68 Found : C, 60.41; H, 4.89; N, 6.85 Example 18 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester S-oxide To a solution of 3,5-trans-7-chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (1 g) obtained in Example 3 in dichloromethane (10 ml) was added metachloroperbenzoic acid (0.37 g), which was stirred for 10 minutes at room temperature. To the reaction mixture was added dichloromethane (50 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate, then the aqueous layer was further extracted with dichloromethane. The organic HtC^CE, £64 5 1 - 91 - layer was washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was recrystallized from dichloromethane-hexane to give 0.59 g of colorless crystals, m.p.166-169°C. Elemental Analysis for C23H23C12N04S. 1. 7H20: Calcd.: C, 53.85; H, 5.58; N, 2.73 Found : C, 53.70; H, 5.27; N, 2.36 Example 19 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid S-oxide 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester S-oxide (0.5 g) obtained in Example 18 was allowed to proceed in substantially the same manner as in Example 9 to give 0.38 g of colorless crystals, m.p.230-235°C. Elemental Analysis for C22H23CI2NO4S: Calcd.: C, 56.41; H, 4.95; N, 2.99 Found : C, 56.36; H, 5.04; N, 3.04 Example 20 3,5-trans-7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester S-dioxide CI H3CLj HaCrNa, CI **Nx>off 92 264 5 1 HS<XJ To a solution of 3,5-trans-7-chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (0.3 g) obtained in Example 3 in dichloromethane (10 ml) was addeci metachloroperbenzoic acid (0.25 g), and the mixture was stirred for 2 hours at room temperature, followed by allowing the reaction to proceed in substantially the same manner as in Example 18 to give 1.01 g of colorless crystals, m.p.218-224°C. Elemental Analysis for C^H^C^NOsS: Calcd.: C, 46.14; H, 5.06; N, 2.81 Found : C, 46.22; H, 5.16; N, 2.69 Example 21 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4/l-benzothiazepine-3-acetic acid S-dioxide 3,5-trans-7-Chloro-5- (2-chloropl»enyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid (0.3 g) obtained in Example 9 was subjected to reaction in substantially the same manners as in Example 18 and Example 20 to give 0.14 g of colorless 01 H.C^J B*CT>CB, ^N:oob i 93 264 5 16 crystals, m.p.245-249°C. Elemental Analysis for C^H^CljNOjS. 0. 2HZ0: Calcd.: C, 54.15; H, 4.83; N, 2.87 Found : C, 54.08; H, 4.83; . N, 2.65 Example 22 N-[3,5-trans-l-Neopentyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetyl] glycine methyl ester In dichloromethane (2 ml) were dissolved 3,5-trans-7-chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid (0.1 g) obtained in Example 9 and glycine methyl ester hydrochloride (31 mg). To the solution were added, at 0°C, diethyl cyanophosphonate (54 mg) and triethylamine (49 mg). The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added dichloromethane (50 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from dichloromethane/petroleum ether to give 99 mg of colorless crystals, m.p.l88-189°C. Elemental Analysis for CzjI^C^^O.S : Calcd.: C, 57.36; H, 5.39; N, 5.35 Found : C, 57.36; H, 5.39; N, 5.19 94 264 5 1 6 Example 23 N-[3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetyl] glycine The compound obtained in Example 22 (50 mg) was subjected to hydrolysis in substantially the same manner as in Example 9 to give 35 mg of colorless crystals, m.p.229-230°C. Elemental Analysis for C2iiH26Cl2N20AS . 0 . 3H20: Calcd.: C, 55.99; H, 5.21; N, 5.44 Found : C, 55.98; H, 5.09; N, 5.29 Example 24 3,5-trans-7-Chloro-5-(2-chlorophenyl)-3-dimethylaminocarbonylmethyl-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine To a solution of 3•5-trans-7-chioro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acatic acid (1 g) obtained in Example 9 and dimethylamine hydrochloride (0.2 g) in dichloromethane (20 ml) were added diethyl cyanophosphomate (375 mg) and triethylamine (558 mg). The mixture was stirred for 30 minutes at room JHS - 95 - 2645 1 6 temperature. To the reaction mixture was added dichloromethane (100 ml), which was washed with 5% HC1, a saturated aqueous solution of sodium hydrogencarbonate and an aqueous saline solution, then the solvent was distilled off. The residue was recrystallized from dichloromethane/petroleum ether to give 0.98 g of colorless crystals, m.p.190-193°C. Elemental Analysis for C2nH28Cl2N202S: Calcd.: C, 60.12; H, 5.89; N, 5.84 Found : C, 59.99; H, 5.88; N, 5.92 Example 25 7-Chloro-5-(2-chlorophenyl)-l-isobutyl-2-oxo-2,3,4,5-tetrahydro-lH-[l]-benzazepine-3-acetic acid ethyl ester In accordance with the method disclosed in J. Med. Chem., 27, 1508 (1984), J. Med. Chem., 14., 851 (1971), the following intermediate compounds were synthesized. (1) 3-(ethoxycarbonyl)-4-(2-chlorophenyl)-4-phenyl-3-butenic acid, an oily compound IR v ^(neat) cm"1: 1730, 1715, 1705. (2) 4-(2-Chlorophenyl)-4-phenylbutyric acid ethyl ester an oily compound IR v ^(neat) cm"1: 1730. 1H-NMR(CDC13) 6: 1.23(3H,t,J=7.1Hz), 2.2-2.5(4H,m), 4.10(2H,q,J=7.1Hz), 4.45-4.6(lH,m), 7.0-7.4(9H,m) (3) 4-(2-Chlorophenyl)-4-phenylbutyric acid m.p.133-135°C Elemental Analysis for C16H15C102: Calcd.: C, 69.95; H, 5.50 - 96 - 26 4 5 1 Found : C, 70.10; H, 5.42 (4) 4-(2-Chlorophenyi)-l-tetralone an oily compound IR v ^(neat) cm"1: 1685. 5 ^-NMR (CDC13) 6s 2.2-2.5(2H ,m) , 2 . 6-2 . 8 ( 2H,m) , 4.85(lH,t,J=5.9Hz), 6.7-7.5(7H,m), 8.05-8.2(1H,m) (5) 4-(2-Chlorophenyl)-l-tetralone oxime m.p.114-115°C (6) 5-(2-Chlorophenyl)-2,3,4,5-tetrahydro-lH-[1]-10 benzazepin-2-one m.p.226-227°C Elemental Analysis for Cl6HuClNO: -Calcd.: C, 70.72; H, 5.19; N, 5.15 Found : C, 70.94; H, 5.20; N, 5.20 15 (7) 5-(2-Chlorophenyl)-l-isobutyl-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one To a solution of 5-(2-chlorophenyl)-2,3,4,5-tetrahydro-lH-[l]-benzazepin-2-one (2.8 g) and isobutyl bromide (2.24 ml) in dimethylformamide (20 ml) was 20 added sodium hydride (0.82 g, 60% oil) at 0°C. The mixture was stirred for 4 hours at room temperature, then the solvent was distilled off, and the residue was purified by means of a silica-gel column chromatography to give 2.98 g of colorless crystals, m.p.139-140°C. 25 Elemental Analysis for C2oH22ClNO: Calcd.: C, 73.27; H, 6.76; N, 4.27 Found : C, 73.08; H, 6.69; N, 4.36 (8) 7-Chloro-5-(2-chlorophenyl)-l-isobutyl-2,3,4,5-tetrahydro-lH-[1]-benzazepin-2-one 30 A solution of 5-(2-chlorophenyl)-1-isobutyl- 2,3,4,5-tetrahydro-lH-[l]-benzazepin-2-one (2.7 g) and N-chlorosuccinimide (1.65 g) in dimethylformamide (10 ml) was stirred for 7 hours at 7 0°C. To the reaction mixture was added acetic acid ethyl ester (100 ml), 35 which was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, 2 6 4 5 1 $ followed by drying over anhydrous sodium sulfate. The solvent was removed, and the residue was recrystallized from hexane/acetic acid ethyl ester to give 2.39 g of colorless crystals, m.p.152-154°C. 5 (9) 7-Chloro-5-(2-chlorophenyl)-l-isobutyl-2-oxo- 2,3,4,5-tetrahydro-lH-[1]-benzazepine-3-acetic acid ethyl ester To dry tetrahydrofuran (5 ml) was added isopropylamine (0.25 ml), and the mixture was cooled to 10 -15°C, to which was added a 1.58M hexane solution of n-butyl lithium (1.14 ml), and the mixture was stirred for 45 minutes at -15°C. To the reaction mixture was added 7-chloro-5-(2-chlorophenyl)-2,3,4,5-tetrahydro-lH-[l]-benzazepin-2-one (0.5 g) dissolved in 15 tetrahydrofuran (5 ml), which was stirred for 15 minutes at 0°C. The reaction mixture was cooled to -78°C, to which was added iodoacetic acid ethyl ester (0.25 ml). The mixture was stirred for 15 minutes at -7 8°C, then for one hour at 0°C. To the reaction 20 mixture was added 1H hydrochloric acid (50 ml), which was extracted with acetic acid ethyl ester. The acetic acid ethyl ester layer was washed with a saturated aqueous solution of hydrogencarbonate, followed by drying over anhydrous magnesium sulfate. The solvent 25 was distilled off, and the residue was purified by means of a silica-gel column chromatography to give 0.1 g of an oily compound. IR Voax(neat)cm'1: 1730, 1660. 1H-NMR (CDC13) 6: 0.5-1.15(6H,m), 1.15-1.4(3H,m), 1.7-30 3.1(5H,m), 3.1-3.9(2H,m), 4.0-4.1(2H,m), 4.4-4.8(lH,m), 6.4-7.6(7H,m) SIMS (m/z) : 449 (MH+) Example 26 7-Chloro-5-(2-chlorophenyl)-l-isobutyl-2-oxo-2,3,4,5-35 tetrahydro-lH-[l]-benzazepine-3-acetic acid - 98 - 264516 C3 OH The compound (90 mg) obtained in Example 25 was allowed to proceed in substantially the same manner as in Example 9 to give 50 mg of colorless crystals, m.p.165-171°C. Elemental Analysis for C22H23CI2NO3: Calcd.: C, 62.86; H, 5.51; N, 3.33 Found : C, 62.77; H, 5.61; N, 3.29. Example 27 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,4-tetrahydro-2-thioxo-4,l-benzoxazepine-3-acetic acid ethyl ester A solution of 3,5-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-l,2,3,4-tetrahydro-4 ,l-benzoxazepine-3-acetic acid ethyl ester (1.0 g) and Lawesson's reagent (1.3 g) in toluene (15 ml) was heated for 8 hours under reflux. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography to give 0.68 g of yellow crystals, m.p.200-201°C. Elemental Analysis for C24H27CI2NO3S: Calcd.: C, 60.00; H, 5.66; N, 2.92 hacsj H3C1 CHS - 99 - 264 5 16 Found : C, 60.10; H, 5.78; N, 2.65 Example 28 3,5-trans-7-Chl.oro-5- ( 2-chlorophenyl) -1-neopentyl-1,2,3,4-tetrahydro-2-thioxo-4,l-benzoxazepine-3-acetic acid "-The compound (0.4 g) obtained in Example 27 was allowed to proceed in substantially the same manner as in Example 9 to give 0.1 g of yellow crystals, m.p.248-249 °C. Elemental Analysis for C^H^ClzNC^S: Calcd.: C, 58.41; H, 5.12; N, 3.10 Found : C, 58.48; H, 5.33; N, 3.01 Example 29 3,5-trans-7-Chloro-5-(2-chlorophenyl) -1,2,3,5-tetrahydro-2-thioxo-4,1-benzothiazepine-3-acetic acid methyl ester 3,5-trans-7-Chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid ethyl ester (1.0 g) obtained in Example 1 was allowed to proceed in substantially the same manner as in Example 27 to give 0.95 g of yellow crystals, m.p.194-197 °C. - 100 - 26 4 5 1 P- Elemental Analysis for C18H15C12N02S2: Calcd.: C, 52.43; H, 3.67; N, 3.40 Found : C, 52.41; H, 3.53; N, 3.10 Example 3 0 7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,3,5-tetraydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester H.O (1) 5-Chloro-3-(2-chlorobenzoyl)-2-10 neopentylaminorhiophene In a mixture solvent of methanol (200 ml) and acetic acid (100 ml) was dissolved 2-amino-5-chloro-3-(2-chlorobenzoyl)thiophene (10.89 g). To the solution were added pivalaldehyde (8.69 ml) and molecular sieves 15 3A (0.5 g). The mixture was stirred for 2 hours at 60°C, to which was added dropwise a solution of sodium cyanoborohydride. (2.51 g) in methanol (10 ml), and the mixture was stirred for 2.5 hours at room temperature. The solvent was distilled off. The residue was 20 dissolved in acetic acid ethyl ester. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of a silica-25 gel column chromatography to give 4.85 g of pale yellow crystals, m.p.74-76°C. Elemental Analysis for C16H17C12N0S: Calcd.: C, 56.14; H, 5.01; N, 4.09 Found : C, 56.18; H, 5.17; N, 3.89 30 (2) 3-[N-[5-Chloro-3-(2-chlorobenzoyl)-2-thienyl]-N- - 101 - 264 5 1 ?■ neopentylcarbamoyl]acrylic acid ethyl ester To a solution of 5-chloro-3-(2-chlorobenzoyl)-2-neopentylaminothiophene (4.85 g), triethylamine (5.92 ml) and a small amount of dimethylaminopyridine in 5 dimethylformamide (60 ml) was added dropwise a solution of fumaric chloride monoethyl ester (4.60 g) in dimethylformamide (20 ml). The reaction mixture was stirred overnight at room temperature, which was poured into water, followed by extraction with acetic acid 10 ethyl ester. The extract solution was washed with 1 M aqueous solution of potassium hydrogen sulfate and a saturated aqueous saline solution, followed by drying over., anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by a silica-15 gel column chromatography, followed by recrystallization from hexane/acetic acid ethyl ester to give 4.3 g of colorless crystals, m.p.79-81°C. Elemental Analysis for C^H^Cl^O/iS. 0 . 5H20: Calcd.: C, 55.35; H, 5.07; N, 2.93 20 Found : C, 55.25; H, 4.83; N, 3.00 (3) 3-[N-[5-Chloro-3-(a-hydroxy-2-chlorobenzyl)-2-thienyl]-N-neopentylcarbamoyl]acrylic acid ethyl ester To a solution of 3-[N-[5-chloro-3-(2-chlorobenzoyl)-2-thienyl]-N-neopentylcarbamoyl]acrylic 25 acid ethyl ester (2.37 g) and cesium trichloride.heptahydrate (2.98 g) in methanol (100 ml) was gradually added, sodium borohydride (303 mg) at room temperature. The mixture stirred for 20 minutes at room temperature, to which was added acetone, then 30 the solvent was distilled off. To the residue were added IM potassium hydrogensulfate and acetic acid ethyl ester. The organic layer was washed with a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was 35 distilled off, and the residue was purified by means of a silica-gel column chromatography to give a non- - 102 - 264 51 6 crystalline solid (2.47 g). ^-NMR (CDC13) S: 0.91, 1.00(9H), 1.20-1.35(3H,m), 2.50-2.59(lH,m), 2.90-4.28(4H,m), 5.95, 6.05(total IH), 6.52-7.60(7H,m) 5 (4) 7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo- 1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3~acetic acid ethyl ester To a solution of 3-[N-[5-chloro-3-(a-hydroxy-2-chlorobenzyl)-2-thienyl]-N-neopentylcarbamoyl]acrylic 10 acid ethyl ester (2.37 g) in ethanol (50 ml) was added potassium carbonate (700 mg). The mixture was stirred for 8 hours at room temperature. The reaction mixture was-poured into water, which was extracted with acetic acid ethyl ester. The extract solution was washed with 15 a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by means of a silica-gel column chromatography to give a pale yellow oily compound (1.73 g). 20 1H-NMR (CDCI3) S: 0.99, 1.02(9H,each s), 1.26, 1.28(3H,each t), 2.60-3.09(3H,m), 4.08-4.25(2H,m), 4.38, 4.57(IH,each d), 4.67, 4.92(lH,each dd), 5.87, 6.42(lH,each s), 6.06, 6.51(lH,each s), 7.20-7.66(4H,m) Example 31 25 3,5-trans-7-Chloro-5- (2-chlorophenyl) -lr-neopentyl-2- oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]benzoxazepine-3-acetic acid The compound obtained in Example 30 (1.64 g) was dissolved in a mixture solvent of methanol (30 ml) and 30 tetrahydrofuran (30 ml). To the solution was added - 103 - ? 6 4 5 1 fi potassium carbonate, which was then stirred for 2 hours at 60°C. The reaction mixture was made acid with IN hydrochloric acid, which was then poured into water, followed by extraction with acetic acid ethyl ester. 5 The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of a silica-gel column chromatography to give a solid matter, which was recrystallized from hexane/acetic acid ethyl ester to 10 give 68 mg of colorless crystals, m.p.202-204°C Elemental Analysis for C20H21C12NOAS: Calcd.: C, 54.30; H, 4.78; N, 3.17 -Found : C, 54.20; H, 4.62; N, 3.16 Example 32 15 3,5-trans-7-Chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester and 3,5-cis-7-chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester 20 l^C00Cih n y^COOCaHs HsCKXBs In substantially the same manner as in Example 30, these compounds were produced. (1) 5-Chloro-3-(2-methoxybenzoyl)-2-neopentylamino 25 thiophene m.p.117-118°C. Elemental Analysis for C17H20C1N02S: Calcd.: C, 60.43; H, 5.97; N, 4.15 Found : C, 60.15; H, 5.92; N, 4.10 - 104 - 264516 ( 2) 3 - [N- [ 5-Chloro-3-( 2-methoxybenzoyl) -2-thienyl ] -N-neopentylcarbaxnoyl]acirylic acid ethyl ester an oily compound lH-NMR(CDCl3) £: 0.96(9H,s), 1.26(3H,t,J=7.2Hz), 5 3.57(lH,d,J=13.7Hz), 3.73(3H,s), 3.74(lH,d,J=13.7Hz), 4.18(2H,q,J=7.2Hz), 6.75(lH,s), 6.81(lK,d,J=15.3Hz), 6 .90-7.04(2H,m), 7.12(lH,d,J=15.3Hz), 7.31-7.51(2H,m) (3) 3-[N-[5-Chloro-3-(a-hydroxy-2-methoxybenzyl)-2-thienyl]-N-neopentylcarbamoyl]acrylic acid ethyl ester 10 an oily compound 1H-NMR(CDC13) 6: 0.91, 1.00(9H,each s), 1.24, 1.28(3H,each t), 2.80-2.91, 3.32(1H), 3.74, 3 .82-( 3H,each s), 4 .06-4 .27 (3H,m), 5.81, 5.93(lH,each d), 6.40-7.34(7H,m) 15 (4) 3,5-trans-7-Chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester m.p.148-150°C Elemental Analysis for C^^ClNOsS: 20 Calcd.: C, 59.28; H, 6.06; N, 3.01 Found : C, 59.17; H, 5.95; N, 2.90 3,5-cis-7-Chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester 25 1H-NMR(CDC13) 6: 0.97(9H,s), 1.26(3H,t,J=7.1Hz), 2.81(lH,dd,J=8.1,17.0Hz), 2.96(lH,d,J=14.2Hz ), 3.01(lH,dd,J=5.8,17.0Hz), 3.89(3H,s), 4.10-4.23(2H,m), 4.54(lH,d,J=14.2Hz), 4.90(lH,dd,J=5.8,8.1Hz), 6.42(lH,s), 6.56(lH,s), 6.88-6.97(2H,m), 7.22-30 7.32(lH,m), 7.35-7.41(lH,m) Example 33 3,5-trans-7-Chloro-5- (2-methoxyphenyl) - 1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid - 105 - 264 S1 6 The trans-form ethyl ester (0.51 g) obtained in Example 32 was allowed to proceed in substantially the same manner as in Example 31 to give 0.18 g of colorless crystals, m.p.2'20-222°C. Elemental Analysis for C21H24C1N05S: Calcd.: C, 57.59; H, 5.52; N, 3.20 Found : C, 57.54; H, 5.58; N, 3.18 Example 34 3,5-cis-7-Chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid The cis-form ethyl ester obtained in Example 32 (0.28 g) was allowed to proceed substantially the same manner as in Example 31 to give 0.16 g of colorless crystals, m.p.l89-191°C Elemental Analysis for C21H2AC1N05S: Calcd.: C, 57.59; H, 5.52; N, 3.20 Found : C, 57.36; H, 5.42; N, 3.11 2645^5 Example 35 3,5-trans-7-Chloro-l-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester and 3,5-cis-7-chloro-l~ 5 isobutyl-5-(2-methoxyphenyl)-2-oxo-l,2,3,5-tetrahydro- 4,l-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester c^jpooc,., cl-ftqo^coocsh, These compounds were produced in substantially the same manner as in Example 30. (1) 5-Chloro-2-isobutylamino-3-(2- ra.p.83-84°C Elemental Analysis for C16H18C1N02S: Calcd.: C, 59.34; H, 5.60; N, 4.33 Found : C, 59.41; H, 5.63; N, 4.30 15 (2) 3-[N-[5-Chloro-3-(2-methoxybenzoyl)-2-thienyl]-N-isobutylcarbamoyl]acrylic acid ethyl ester an oily compound ^-NMRfCDCla) 6: 0.92(6H,br), 1.28(3H,t,J=7.1Hz), 1.89-2.12(lH,m), 3.12-3.27(lH,m), 3.75(3H,s), 3.80-4.00(lH,m), 4.20(2H,q,J=7.1Hz), 6.76-20 7.54(7H,m) (3) 3-[N-[5-Chloro-3-(a-hydroxy-2-methoxybenzyl)-2-thienyl]-N-isobutylcarbamoyl]acrylic acid ethyl ester ^-NMR(CDC13) 6: 0.80-1.00(6H,m), 1.19-1.32(3H,m), 25 .1.88-2.16(lH,m), 2.69-3.24(2H,m), 3.74,3.79(3H,each s), 3.87-4.26(3H,m), 5.80-5.99(lH,m), 6.49-7.64(7H,m) (4) 3,5-trans-7-Chloro-l-isobutyl-5-(2-methoxyphenyl)-2-oxo-l,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3- 10 me thoxybenz oy1)thiophene an oily compound 107 264 5 1 acetic acid ethyl ester m.p.126-128°C 5 Elemental Analysis for C22H26C1N05S: Calcd.: C, 58.46; H, 5.80; N, 3.10 Found : C, 58.23; H, 5.72; N, 3.03 3,5-cis-7-Chloro-l-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,l-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester an oily compound 10 1H-NMR(CDC13) 6: 0.96(6H,d,J=6.6Hz), 1.27(3H,t,J=7.1Hz), 2.05-2.24(lH,m), 2.81(lH,dd,J=8.1,17.0HZ), 3.00(lH,dd,J=5.6,17.0Hz ) , 3 . 09-( lH,dd, J=5 .3,14.1Hz) , 3 .88(3H,s) , 4.17(2H,q,J=7.1Hz), 4.31(lH,dd,J=9.3,14.1Hz), 15 4.89(IH,dd,J=5.6,8.1Hz), 6.41(lH,s), 6.48(lH,s), 6.86-6.96(2H,m), 7.20-7.34(2H,m) Example 3 6 3,5-trans-7-Chloro-l-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-20 acetic acid The trans-form ester (0.68 g) obtained in Example 35 was allowed to proceed in substantially the same manner as in Example 31 to give 0.22 g of colorless crystals, m.p.183-185°C. 25 Elemental Analysis for C20H22ClNO5S: Calcd.: C, 56.67; H, 5.23; N, 3.30 Found : C, 56.40; H, 5.18; N, 3.29 - 108 - ? 6 4 5 1 6 Example 37 3,5-cis-7-Chloro-l-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid CHj The cis-form ester (0.59 g) obtained in Example 35 was"allowed to proceed in substantially the same manner as in Example 31 to give 0.27 g of a colorless solid matter, m.p.144-146°C. Elemental Analysis for C20H22C1N05S: Calcd.: C, 56.67; H, 5.23; N, 3.30 Found : C, 56.94; H, 5.24; N, 3.58 Example 38 3,5-trans-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester 5-Chloro-a-(2,3-dimethoxyphenyl)-2-(neopentyl-amino)benzyl alcohol (1.0 g) and thiomalic acid (0.41 g) were subjected to substantially the same procedure as in Example 1 to give 0.38 g of colorless crystals, m.p.193-196°C. Elemental Analysis for C25H30ClNO5S • 0. 3H20: Calcd.: C, 60.36; H, 6.20; N, 2.86 264516 - 109 - Found : C, 60.43; H, 6.21; N, 2.75 Example 39 3,5-trans-7-Chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl- 3,5-t'rans-7-Chloro-5- ( 2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-l., 2,3,5-tetrahydro-4, 1-benzothiazepine-3-acetic acid methyl ester obtained in Example 38) (10 g) was subjected to substantially the same procedure as in Example 9 to give 7.7 g of colorless crystals, m.p.263-277°C. Elemental Analysis for C2AH28C1N05S: Calcd.s C, 60.31? H, 5.91; N, 2.93 Found s C, 60.03; H, 5.86; N, 2.84 Example 40 N-[(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tatrahydro-4,1-benzothiazepine-3-acetyl]-L-leucine methyl ester and N-[ (3S,5Ft) —7— chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl)-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetyl]-L-leucine methyl ester iuoJ lUC^CHa 26451 R Ce! OMe Me L- LeuOCHj - L- LeuOCHj w 1 CIla In dichloromethane (150 ml) were dissolved 3,5-trans-7-chloro-5-(2,3-dimethoxypheny1)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid (7.1 g) and L-leucine methyl ester (2.7 g). To 5 the-solution were added diethyl cyanophosphonate (3.6 g) and triethylamine (3.3 g). The mixture was stirred for 30 minutes at room temperature, which was then washed with 5% HC1, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline 10 solution. The solvent was then distilled off, and the residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester = 4:1 -3:1 v/v as an eluent) to give 4.13 g of N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-l-neopentyl-2-oxo-15 1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetyl]-L-leucine methyl ester from the first fraction as colorless crystals, m.p.l21-123°C. [a]DZ2-235.2° (c=0.39, MeOH) ^-NMRfCDCla) 6 : 0.932(6H, t, J=6.2Hz), 0.989 20 (9H,s), 1.49-1,67(3H,m), 2.322(lH,dd,J=3.2, 14.2Hz), 2.97(lH,dd,J=10.6,14.2Hz) 3.187(lH,d,J=14.0Hz), 3.696(3H,s), 3. 715(3H,s), 25 3.779(lH,dd,J=3.2,10,6Hz), 3.889(3H,s), 4.420(lH,d,J=l4,0Hz), 4.47-4.59(lH,m), 6.05-6.10(lH,br) 6.270(lH,s), 6.814-7.400(6H,m) Ill ?64 5 1 6 From the second fraction was obtained 4.15 g of N-[(3S,5R)-7-chloro-5-(2,3-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetyl]-L-leucine methyl ester as a non-crystalline solid product. [a]D22+178. 6 deg. (c=0.47, MeOH) 1H=NMR(CDC13) S: 0. 89-0.92 (6H,m), 0.996(911,8), 1.51- Example 41 (3R/5S)-7-Chloro-5-(2,3-dimethoxyphenyl) - l-neopentyl-2-oxo-1/2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester To a solution of N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl- 2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetyl]-L-leucine methyl ester (4.13 g) obtained in Example 40 in methanol (100 ml). To the solution was added conc. HC1 (50 ml), and the mixture was heated for 24 hours under reflux. The reaction mixture was subjected to extraction with uichloromethane, and the extract was dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was purified oy means of a 1.66(3H,m), 2.323(lH,dd,J=4.2,14.4Hz), 2.990(lH,dd,J=10.2,14.4Hz), 3.226(lH,d,J=13.8Hz), 3.69-3.78(7H,m), 3.890(3H,s), 4.44-4.54(2H,m), 6.281(IH,s), 6.37-6 .41(IH,br), 6.801-7.396(6H,m) •Oile OHe ^vcoocn3 112 264 5 16 silica-gel column chromatography (acetic acid ethyl ester = 3 s 1 v/v as an eluent). The solid product thus obtained was recrystallized from a mixture solvent of dichloromethane-petroleum ether to give 2.87 g of Example 42 (3S,5R)-7-Chloro-5-(2,3-dimethoxyphenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetyl]-L-leucine methyl ester (4.15 g) obtained in Example 40 was subjected to substantially the same procedure as in Example 41 to give 2.70 g of colorless 15 crystals, m.p,168-170°C. Example 43 (3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid 5 colorless crystals, m.p.170-171°C. 10 N-[(3S,5R)-7-Chloro-5-(2,3-dimethoxyphenyl)-1- 20 (3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1- - 113 - 264516 neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (2.6 g) obtained in Example 41 was subjected to substantially the same procedure as in Example 9 to give 1.98 g of colorless crystals, 5 m.p.263-271°C. [a]D22-303.5° (c=0. 92, MeOH) Elemental Analysis for C24H28C1N05S: Calcd.: C, 60.31; H, 5.90; N, 2.93 Found : C, 60.09; H, 6.08; N, 2.99 10 Example 44 (3S,5R)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid- aOJlc OMe (3S,5R)-7-Chloro-5-(2,3-dimethoxyphenyl)-l-neopentyl-2- 15 oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester (2.5 g) obtained in Example 42 was subjected to substantially the same procedure as in Example 9 to give 1.88 g of colorless crystals, m.p.261-270°C. 20 [a]DZ2+290.2° (c=0.61, MeOH) Elemental Analysis for C2AH28C1N05S: Calcd.: C, 60.31; H, 5.90; N, 2.93 Found : C, 60.13; H, 5.89; N, 2.97 Example 4 5 25 3.5-trans-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester - 114 - 264516 Olfe 5-Chloro-a- (2,4-dimethoxyphenyl) -2- (neopentyl amino)benzyl alcohol (38.9 g) and thiomalic acid (16.1 g) were subjected to substantially the same procedure as in Example 1. to give 32.5 g of colorless crystals, m.p.190-191°C. Elemental Analysis for C25H30ClNO5S: Calcd.: C, 61.03; H, 6.15; N, 2.85 Found : C, 60.95; H, 6.12; N, 2.75 Example 46 3,5-trans-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid Oile CHj 3,5-trans-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (27 g) obtained in Example 45 was subjected to substantially the same procedure as in Example 9 to give 26.6 g of colorless crystals, - 115 - 264516 m.p.157-160°C. Elemental Analysis for C„H28C1N03Ss Calcd.: C, 60.31; H, 5.91; N, 2.93 Found : C, 60.57; H, 5.83; N, 2.66 Example 47 N-[(3S,5R)-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetyl]-L-alanine tert-butyl ester and N-[(3R,5S)-7- " chloro-5-(2,4-dimethoxyphenyl)-4-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetyl]-L-alanine tert-butyl ester OHe c^-OKe cioi3rc°-l-aia°bu n3Cyl IljCcn3 3,5-trans-7-Chlorp-5- (2,4-d.imethoxyphenyl) -1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid (15 g) and L-alanine tert-butyl ester hydrochloride (6.0 g) were subjected to substantially the same procedure as in Example 40 to give 6.31 g of N-[3S,5R)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-l ,2,3 ,.5-tetrahydro-4, l-benzothiazepine3-acetyl ] -L-alanine tert^-butyl ester as a non-crystalline solid product from the first fraction. 1H-NMR(CDC13) S: 0.975(9H,s), 1.322(3H,d,J=7.0Hz), 1.463(9H,s), 2.300(lH,dd,J=3.8,14.6Hz), 2.993(lHydd,J=10.0, 14.6Hz), 3.205(lH,d,J=13.8Hz), 3.663(3H,s), 3.713(lH,dd,J=3.8,10.0Hz), OUe - 116 - 264 5 1 6 . 3.858(3H,s), 4.358(lH,q,J=7.0Hz), 4.472(lH,d/J=13.8Hz), 6.243(lH,s), 6.471(lH,dfJ=2.4Hz), 6.606(lH,dd,J=2.4, 8.4Hz), 5 6.836(lH,d,J=1.8Hz), 7.264(2H,m), 7. 624(lH,d,J=8.6Hz) From the second fraction was obtained 7.91 g of N-[(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzothiaxepine-10 3-acetyl]-L-aalanine tert-butyl ester as a noncrystalline solid product. ^-NMR(CDC13) 8: 0.968(9H,s), 1.338(3H,d,J=7.0Hz), 1.440(9H,s), 2.332(lH,dd,J=3.6,15.2Hz), 15 2.937(lH,dd,J=10.4,15.2Hz), 3.186(lH,d,J=13.8Hz), 3.660(3H,s), 3.781(lH,dd,J=3.6,10.4Hz), 4.369(lH,q,J=7.0Hz), 4.447(1H,d,J=13.8Hz), 6.240(1H,s), 20 6.470(lH,d,J=2.4Hz), 6.603(lH,dd,J=2.4, 8,6Hz), 6.841(lH,s), 1.264(2Hrm), 7.629(lH,d,J=8.6Kz) Example 48 25 (3S,5R)-7-Chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester COOClIj N-[(3S,5R)-7-chloro-5-(2,4-dimethoxypheriyl)-1- - 117 - 2 6 4 5 1 6 neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-eortyl]-L-alanine tert-butyl ester (6.31 g) obtained in Example 47 was subjected to substantially the same procedure as in Example 41 to give 4.0 g of colorless crystals, m.p.187-188°C. Example 49 (3R,5S)-7-Chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester Olle N-f(3R,5S)-7-Chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetyl]-L-alanine tert-butyl ester (7.91 g) obtained in Example 47 was subjected to substantially the same procedure as in Example 41 to give 3,89 g of colorless crystals, m.p.188-190°C. Example 50 (3S,5R)-7-Chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid OMe & OMe CI COOH ][^u 2 6 4 5 'i 118 (3S,5R)-7-Chloro-5-(2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (3.5 g) obtained in Example 48 was subjected to substantially the same procedure as in Example 9 to give 3.22 g of colorless crystals, m.p.147-151°C. [a]D22+255.9° (c=0.35, MeOH) Elemental Analysis for C24H28C1NOsS : Calcd.: C, 60.31; H, 5.91; N, 2.93 Found : C, 60.58; H, 5.82; N, 2.79 Example 51 (3R,5S)-7-Chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo—1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid (3R,5S)-7-Chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (3.37 g) obtained in Example 49 was processed in substantially the same manner as in Example 9 to give 3.28 g of colorless crystals, m.p.148-152°C. [a]D22 -252.3° (c=0 . 47, MeOH) Elemental Analysis for C2/jH28ClN05S: Calcd.: C, 60.31; H, 5.91; N, 2.93 Found : C, 60.32; H, 5.83; N, 2.87 Example 52 7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,4,5-tetrahydro-3H-l,3-benzodiazepine-3-acetic acid methyl CJJ3 - 119 - 264516 ester (1) a-(5-Chloro-2-nitrophenyl)-2-chlorophenylacetic acid methyl ester A solution of sodium hydride (3.4 g), 2-5 chlorophenyl acetic acid methyl ester (28.3 g) and 4-chloro-1,2-dinitrobenzene (27 g) in dimethylformamide (100 ml) was stirred for one hour at 0°C. The reaction mixture was added to dilute hydrochloric acid (300 ml)f followed by extraction with acetic acid ethyl ester. 10 The extract solution was washed with a saturated aqueous saline solution, dried over anhydrous sodium sulfate, and, then the solvent was distilled off. The residual oily product was purified by means of a silica-gel column chromatography (hexane : acetic acid 15 ethyl ester =.10:1 v/v as an eluent), followed by recrystallization from hexane to give 26.3 g of yellow crystals, m.p.96-97°C. Elemental Analysis for C15HuCl2NO/i: Calcd.: C, 52.96; H, 3.26; N, 4.12 20 Found : C, 53.04; H, 3.34; N, 4.06 (2) 2-(2-Nitro-5-chlorophenyl)-2-(2-chlorophenyl)ethanol A mixture solution of a-(5-chloro-2-nitrophenyl)-2-chlorophenyl acetic acid methyl ester (26.3 g) and 25 lithium borohydride (2 g) in tetrahydrofuran (200 ml) was stirred for 4 hours at room temperature. This mixture solution was added to a 20% aqueous solution of acetic acid (50 ml), which was extracted with acetic - 120 - 264 5 1 6 acid ethyl ester. The extract solution was washed with water, dried over anhydrous sodium sulfate and, then, the solvent was distilled off. The residual oily compound was purified by means of a silica-gel column 5 chromatography to give 11.0 g of an oily compound. 1H-NMR(CDC13) S: 1.90(lH,br), 4.15-4.33(2H,m), 5.270 (lH,t,J=6.2Hz), 7.20-7.40(6H,m), 7.867(lH,d,J=8.4Hz) (3) a-(5-Chloro-2-nitrophenyl)-2-chlorophenyl 10 acetaldehyde A solution of dimethyl sulfoxide (6.7 ml) in dichloromethane (30 ml) was added to a solution of oxalyl chloride (6.2 ml) in dichloromethane (300 ml) at -78°C. The mixture was stirred for further 10 minutes 15 at -78°C. To the solution was added a solution of 2-(2-nitro-5-chloropheny.l) -2- (2-chlorophenyl) ethanol (11.04 g) in dichloromethane (100 ml) at -78°C, and the mixture was stirred for further 15 minutes at -7 8°C. To the reaction mixture was added triethylamine 20 (37 ml), which was warmed up to 0°C, to which was added a saturated aqueous solution of ammonium chloride (124 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and, then, the solvent was distilled off. The residual oily compound was 25 purified by means of a ssilica-gel column chromatography (hexane : acetic acid ethyl ester = 3:1 v/v as an eluent) to give 9.15 g of an oily compound. ^-NMR(CDC13) 5 : 6.299(lH,s), 6.836(lH,d,J=2.2Hz), 7.14-7.65(5H,m), 30 8.096(lH,d,J=88Hz), 9.887(lH,s) (4) N- [ 2- (2-Chl'orophenyl) -2- (2-nitro-5-chlorophenyl)ethyl]glycine methyl ester To a solution of a-(5-chloro-2-nitrophenyl)-2-chlorophenylacetaldehyde (1.68 g) in methanol(15 ml) 35 were added glycine methyl ester hydrochloride (0.69 g) and sodium acetate (0.45 g). The mixture was stirred - 121 - 264516 for 30 minutes at room temperature, to which was added • sodium cyanoborohydride (0.35 g). To this mixture was added hydrogen chloride for 5 minutes. This mixture solution was stirred for 3 hours at 50°C, to which was added a IN aqueous solution of sodium hydroxide (50 ml) /^followed by extraction with clichloroiiiethaneThe extract solution was washed with water, then the solvent was distilled off. The residual oily product was purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester = 3:1 v/v as an eluent) to give 1.1- g of an oily compound. 1H-NMR(CDC13) S: 3.200(lH,dd,J=6.8,12.2Hz), 3.366(lH,dd,J=7.6,12.2Hz), 3 .482(2H,s), 3.731(3H,s), 5.255(lH,t,J=7.2Hz), 7.22-7.44(6H,m), 7.846(lH,d,J=8.6Hz) (5) N-[2-(2-chlorophenyl)-2-(2-nitro-5-chlorophenyl) ethyl ] -N- (trif luoroacetyl) glycine methyl ester To a solution of N-[2-(2-chlorophenyl)-2-(2-nitro-5-chlorophenyl)ethyl]glycine methyl ester (4.9 g) and pyridine (3.0 g) in dichloromethane (50 ml) was added trifluoroacetic anhydride (2.97 g), and the mixture was stirred for 10 minutes at room temperature. The solution was washed with a IN aqueous solution of sodium hydroxide and a saturated aqueous saline solution, which was then dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester = 5:1 v/v as an eluent) to give 5.95 g of an oily compound. 1H-NMR(CDC13) 6: 3.786(3H,s), 4.138(lH,dd,J=7.0, 14.0 Hz), 4.215(2H,s),. 4.434(lH,dd,J=8.8, 14.0Hz), 5.473(lH,dd,J=7.0, 8.8Hz), 7.27-7 .52(6H,m), 7.874(lH,d,J=8.4Hz) 2 6 4 5 16 - 122 - (6) N-[2-(2-Amino-5-chlorophenyl)-2-(2- chlorophenyl)ethyl]-N-(trifluoroacetyl)glycine methyl ester To a solution of N-[2-(2-chlorophenyl)-2-(2-nitro-5 5-chlorophenyl)ethyl]-N-(trifluoroacetyl)glycine methyl ester (1 g) in acetic acid ethyl ester (20 ml) was added 10% Pd/C catalyst (100 mg). The mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. After the reaction, the 10 catalyst was removed and the solvent was distilled off. The residue was purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester - 4jJ. v/v as an eluent) to give 0.39 g of an oily compound. 15 1H-NMR(CDC13) S: 3.705 (1/4 x 3H,s), 3.742 (3/4 x 3H,s), 3.473-4.247(4H,m), 4.72-4.80(1/4 x lH,m), 4.874(3/4 x IH, dd, J=5.8, 9.4Hz), 6.57-6.63(7H,m), 7.05-7.44(6H,m) 20 (7) N-[2-(5-Chloro-2-neopentylaminophenyl)-2-(2- chlorophenyl)ethyl]-N-trifluoroacetylglycine methyl ester To a solution of N-[2-(2-amino-5-chlorophenyl)-2-(2-chlorophenyl)ethyl]-N-(trifluoroacetyl)glycine 25 methyl ester (0.39 g) in methanol (5 ml) were added acetic acid (0.05 ml) and pivalaldehyde (78 mg). The mixture was stirred for 30 minutes at room temperature, to which was added sodium cyanoborohydride (57 mg). The mixture was stirred for one hour at room temperature, ^0 followed by addition of dichloromethane (50 ml) thereto. This solution was washed with a IN aqueous solution of sodium hydroxide, then with water, followed by distilling off the solvent. The residue was purified by means of a silica-gel column chromatography 35 - (hexane : acetic acid ethyl ester = 5:1 v/v as an eluent) to give 0.27 g of an oily compound. - 123 - 2 6 4 5 16 1H-NMR(CDC13) S: 0.851(9H,s), 2.65-2.83(2H,m), 3.316(1/4 x lH,d,J=17.4Hz), 3.51-3.60(lH,m), 3.702(1/4 x 3H,s), 3.748(3/4 x 3H,s), 5 3.873(lH,dd,J=9.8, 13,4Hz), 4.055(3/4 x lH,d,J=17.9Hz), 4.274(lH,dd,J=5.8, 13.4 Hz), 4.72-4.86(lH,m), 6.53-6.60(lH,m), 7.11-7.40(6H,m) .1.0 (8) N-[2-(5-Chloro-2-neopentylaminophenyl)-2-(2-chloro phenyl)ethyl]glycine methyl ester To a solution of N-[2-(5-chloro-2-neopentylamino phenyl)-2-(2-chlorophenyl)ethyl]-N- trifluoroacetylglycine methyl ester (0.2 g) in methanol 15 (3 ml) was added conc. hydrochloric acid (0.6 ml), which was heated under reflux for one day. To the reaction mixture was add 2d a IN aqueous solution of sodium hydroxide (8ml), followed by extraction with dichloromethane. The extract solution was washed with 20 water, then the solvent was distilled off to leave 72 mg of an oily compound. 1H-NMR(CDC13) S: 0.823(9K,s), 2.659(lH,d),J=ll.2Hz), 2.769(lH,d,J=ll.2Hz), 3.029(lH,dd,J=5.2,ll.8Hz), 25 3.279(lK,dd,J=8.4,11.8Hz), 3.427(lH,d,17.6Hz), 3.528(lH,d,J=17.6Hz), 3.741(3H,s), 4.563(lH,dd,J=5.2, 8.4Hz), 6.538(lH,d,J=8.8Hz), 6.99-30 7.42(6H,m) (9) 7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-3H-l,3-benzodiazepine-3-acetic acid methyl ester To a solution of N-[2-(5-chloro~2-35 neopentylaminophenyl)-2-(2-chlorophenyl)ethyl]glycine methyl ester (0.47 g) and triethylamine (0.21 g) in 26 4 5 1 6 - 124 - toluene (5 ml) was added triphosgene (0.14 g). The mixture was heated for 5 hours at 70°C. To the reaction mixture was added dichloromethane (50 ml), which was washed with IN hydrochloric acid and water, 5 then the solvent was distilled off. The residue was recrystallized from hexane to give 0.30 g of colorless crystals, m.p.142-148°C. 1H-NMR(CDC13) S: 0.940(9H,s), 3.492(lH,d,J=14.4Hz), 3.639(lH,d,J=17.2Hz) , 3.715 ( 3H, is ), 10 3.876(2H,d,J=8.6Hz), 4.038(lH,d,J=17.2Hz), 4.308(lH,d,J=14.4Hz), 5.317(lH,d,J=8.6Hz), 6.645(lH,d,J=1.8Hz), 7.14-15 7 . 50(6H,m) Example 53 7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,4,5-tetrahydro-3H-l,3-benzodiazepine-3-acetic acid 7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-20 l,2,4,5-tetrahydro-3H-l,3-benzodiazepine-3-acetic acid methyl ester (0.30 g) was processed in substantially the same manner as in Example 9 to give 0.21 g of colorless crystals, m.p.228-231°C Elemental Analysis for C22H2«C12N203: 25 Calcd.: C, 60.70; H, 5.56; N, 6.43 Found : C, 60.37; H, 5.49; N, 6.15 Example 54 3,6-trans-8-Chloro-6-(2-chlorophenyl)-l-neopentyl-2- 264516 oxo-2,3,5,6-tetrahydro-lH-4,l-benzoxazocine-3-acetic acid ethyl ester (1) 2-(2-Amino-5-chlorophenyl)-2-(2-chlorophenyl)ethanol 5 — To a solution of 2-(2-nitro-5-chlorophenyl)-2-(2- chlorophenyl)ethanol (7.0 g) obtained in Example 52-(2) in ethanol (70 ml) were added hydrazine hydrate (3.4 g) and Raney's nickel (0.1 g). The mixture was stirred for 30 minutes at room temperature. The catalyst was 10 removed, and the solvent was distilled off. The residue was purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester = 2:1 v/v as an eluent) to give 4.44 g of an oily compound. 1H-NMR(CDC13) S: 4.107(2H,d,J=6.6Hz), 15 4.587(IH,t,J=6.6Hz), 6.597(lH,d,J=8.4Hz), 7.01-7.43(6H,m) (2) 2-(5-Chloro-2-neopentylaminophenyl)-2-(2-chlorophenyl)ethanol 20 To a solution of 2-(2-amino-5-chlorophenyl)-2-(2- chlorophenyl)ethanol (4.44 g) in methanol (50 ml) were added acetic acid (1.4 ml) and pivalaldehyde (2.0 g). The mixture was stirred for 30 minutes at room temperature. To the solution was added sodium cyano 25 borohydride (1.5 g), and the mixture was stirred for one hour at room temperature. The reaction mixture was then processed in substantially the same manner as in Example 52-(7) to give 5.5 g of an oily compound. - 126 - 2 6 4 5 1 6 ^-NMR(CDC13) 6: 0.813(9H,s), 2.654(lH,d,J=ll.4Hz), 2.766(lH,d,J=ll.4Hz), 4.11-4.15(2H,m), 4.590(1H,t,j=6.3Hz), 6.549(lH,d,J=8.6Hz), 7.01-5 7.44(6H,m) (3) 3-[N-[2-[l-(2-Chlorophenyl)-2-hydroxyethyl]-4-chlorophenyl]-N-neopentylcarbamoyl]acrylic acid ethyl ester To dichloromethane (300 ml) were added 2-(5-10 chloro-2-neopentylaminophenyl)-2-(2- chlorophenyl)ethanol (5.5 g) and sodium hydrogencarbonate (1.7 g). .To the mixture was added fumaric chloride monoethyl ester (2.6 g), which was stirred for one hour at roora temperature. To the _ 15 reaction mixture was added dichloromethane (100 ml), which was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester 20 =5:1 v/v as' an eluent) to give 6.9 g of an oily compound. 1H-NMR(CDC13) S : 0.679(l/2x9H,s), 0.941(l/2x9H,s), 1.210(l/2x3H,t,J=7.2Hz), 1.249(l/2x3H,t,J=7.2Hz), 25 2.300(l/2xlH,d,J=13.8Hz), 2.879(l/2xlH,d,J=13.4Hz), 3.96-4.29(4H,l/2xlH/m), 4.60-4.67(lH,m), 4.821(l/2xlH,t/J=7.0Hz), 5.863(l/2xlH,d,J=15.2Hz), 30 6.l67(l/2xlH,d/J=15.2Hz)/ 6.69- 7.81(8H,m) (4) 8-Chloro-6-(2-chlorophenyl)-l-neopentyl-2-oxo-2,3,5,6-tetrahydro-lH-4,l-benzoxazocine-3-acetic acid ethyl ester 35 To dichloromethane (70 ml) were added 3-[N-[2-[l- (2-chlorophenyl)-2-hydroxyethyl]-4-chlorophenyl]-N- 264516 - 127 - neopentylcarbamoyl]acrylic acid ethyl ester (6.8 g), 18-crown-6 (3.78 g) and potassium carbonate. The mixture was stirred for 3 days at room temperature. Insolubles were filtered off, then the solvent was 5 distilled off. The residue was purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester = 5:1 v/v as 211 eluent) to give 1.64 g of a non-crystalline solid product. ^-NMR(CDC13) 8: 1.028(9H,s), 1.227(3H,t,J=7.2Hz) 10 15 2.740(lH,dd,J=6.6,17.2Hz), 2 . 974(lH,dd,J=7.8,17.2Hz), 3 .716(lH,d,J=13.4Hz), 3.94- 4 .14(5H,m), 4 .417(lH,dd,J=1.4,11,4Hz), 4 . 671(lH,dd,J=1.4, 8.8Hz), 7.014(lH,d,J=2.2Hz), 7.23-7 . 43(6H,m) 20 Example 55 3,6-trans-8-Chloro-6-(2-chlorophenyl)-l-neopentyl-2-oxo-2,3,5,6-tetrahydro-lH-4,l-benzoxazocine-3-acetic acid 26 4 5 1 6 3,6-trans-8-Chloro-6-(2-chlorophenyl)-1-neopentyl-2-oxo-2,3,5,6-tetrahydro-lH-4,l-benzoxazocine-3-acetic acid ethyl ester (1.2 g) obtained in Example 54 was subjected to substantially the same procedure as in Example 9 to give 0.23 g of colorless crystals, m.p.127-133°C. Elemental Analysis for C^H^C^NG*.H20: Calcd.: C, 58.98? H, 5.81; N, 2.99 Found : C, 58.82? H, 5.43; N, 2.97 Example 56 7-Chloro-5-(2-chlorophenyl)-1-neopentyl-1,2-dihydro-2-oxo-3H-l,3,4-benzotriazepine-3-acetic acid ethyl ester (1) 5-Chloro-2-neopentylaminophenyl 2-chlorophenyl thioketone To a solution of 2-amino-2',5-dichlorobenzophenone (10 g) in methanol (50 ml) were added pivalaldehyde (3.4 g) and acetic acid (5 ml). The mixture was stirred for 30 minutes at 0°C. To this solution was added sodium cyanoborohydride (3.1 g), and the mixture was stirred for one day at 60°C. The solution was concentrated, to which was added dichloromethane (100 ml). The mixture was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester = 20:1 v/v as an eluent) to give 6.3 g of a yellow solid compound. To a solution of this compound (0.5 g) in toluene (5 ml) was added a - 129 - 264 5 Lawesson's reagent (0.3 g), and the mixture was heated for two hours under reflux. To the reaction mixture was added acetic acid ethyl ester (50 ml), which was washed with water and then dried over anhydrous sodium 5 sulfate. The solvent was distilled, off to leave'0.54 g of a reddish oily compound. (2) 2-Neopentylamino-2',5-dichlorobenzophenone ethoxycarbonylmethyl hydrazone To a solution of 5-chloro-2-neopentylaminophenyl 10 2-chlorophenyl thioketone (0.54 g) in etha!nol (7ml) was added ethyl hydrazinoacetate hydrochloride (0.11 g). The mixture was stirred'for one day at 70°C. To the reaction mixture was added dichloromethane (50 ml), which was washed with water and, then, dried over 15 anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester = 15:1 v/v as an eluent) to give 0.16 g of an oily product. 20 1H-NMR(CDC13) S: 0.95(9H,s), 1.273(3H,t,J=7.2Hz), 2.964(2H,d,J=5.8Hz), 4.04-4.27(4H,m), 5.969(IH,t,J=5.8Hz), 6.681(lH,d,J=9.0Hz), 6.879(lH,d,J=2.6Hz), 7.15-25 7.50(5H,m) (3) 7-Chloro-5-(2-chlorophenyl)-1-neopentyl-l,2-dihydro-2-oxo-3H-l,3,4-benzotriazepine-3-acetic acid ethyl ester To a solution of 2-neopentylamino-2',5-30 dichlorobenzophenone ethoxycarbonyl methyl hydrazone (0.16 g) and triethylamine (90 mg) in toluene (2 ml) was added triphosgene (54 mg). The mixture was stirred for one hour at 70°C, to which was added acetic acid ethyl estar (50 ml). The mixture was washed with water 35 and, then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was 26451 6 purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester = 3:1 v/v as an eluent) to give 0.16 g of an oily compound. 1H-NMR(CDC13) 8: 0.883(9H,s), 1.238(3H,t,J=7.0Hz), 3,376(lH,d,J-l4.0Hz), 4.184(2H,q,J=7.0Hz), 4.3l9(lH,d,J=16.8Hz), 4.363(lH,d,J=14.0Hz), 4.484(lH/d/J=16. 8Hz), -- — 6 . 857(lH,d,J=2.6Hz), 7.20-7.50(6H,m) Example 57 7-Chloro-5-(2-chlorophenyl)-1-neopentyl-1,2-dihydro-2-oxo-3H-l,3,4-benzotriazepine-3-acetic acid To a solution of 7-chloro-5-(2-chlorophenyl)-l-neopentyl-1,2-dihydro-2-oxo-3H-l,3,4-benzotriazepine-3-acetic acid ethyl ester obtained in Example 56 (0.16 g) in ethanol (3 ml) was added a IN aqueous solution of sodium hydroxide (0.3 ml). The mixture was stirred for 4 hours at room temperature. To the reaction mixture was added water (50 ml), which was made acid with IN HC1, then the solution was concentrated. To the concentrate was added dichloromethane (50 ml), which was washed with water, then the solvent was distilled off. The residue was recrystallized from dichloromethane - petroleum ether to give 91 mg of colorless crystals, m.p.181-183°C. Elemental Analysis for C21H21CI2N3O3: 264 5 16 - 131 - Calcd.: C, 58.07; H, 4.87; N, 9.67 Found : C, 57.90; H, 5.13; N, 9.46 Example 58 315-trans-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-5 3-(tetrazol-5-yl)methyl-l,2,3,5-tetrahydro-4,l-benzothiazepin-2-one OMe (1) 3-[3,5-trans-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1- benzothiazepine-3-acetylamino]propionitrile 10 To a solution of 3,5-trans~7-chloro-5-(2,4- dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine—3-acetic acid obtained in Example 46 (1 g) and 3-aminopropionitrile (150 mg) in dichloromethane (10 ml) were added diethyl 15 cyanophosphonate (340 mg) and triethylamine (320 mg). The mixture was stirred for 10 minutes at room temperature. To the reaction mixture was added dichloromethane (100 ml), which was washed with a IN aqueous solution of NaOH and water, then dried over 20 anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from hexane to give 1.07 g of colorless crystals, m.p.83-103°C. Elemental Analysis for C27H32C1N304S: Calcd.: C, 61.18; H, 6.08; N, 7.93 25 Found : C, 61.41; H, 6.11; N, 7.84 (2) 3,5-trans-7-Chloro-3-[1-(2-cyanoethyl)tetrazol-5-yl]methyl-5-(2,4-dimethoxyphenyl)-1-neopentyl-1,2,3,5- t - 132 - 264516 tetrahydro-4,l-benzothiazepin-2-one 3-[3 ,5-trans-7-Chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,2,5-tetrahydro-4,1-benzothiazepine-3-acetylamino]propionitrile (0.1 g), triphenylphosphine 5 (99 mg), diethyl azodicarboxylate (66 mg) and trimethyl silyl azide (44 mg) in tetrahydrofuran (2 ml) was stirred for one day at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was purified by means of a silica-gel 10 column chromatography (hexane : acetic acid ethyl ester = 1:1 v/v as an eluent) to give 59 mg of a noncrystalline solid compound. 1H-NMR(CDC13) 6: 0.938(9H,s), 2.96-3.16(4H,m), 3.17- 3.52(lH,m), 3.667(3H,s), 15 3.867(3H, s), 3.92-3.99(lH,m), 4.16- 4.28(lH,xn), 4 . 73-4 . 81 ( 2H,m) , 6.290(111,3), 6.49-7.65(6H,m) (3) 3,5-trans-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-3-(tetrazol-5-yl)methyl-l,2,3,5-tetrahydro-20 4,l-benzothiazepin-2-one In a mixture solvent of methanol (1 ml) and tetrahydrofuran (1 ml) was dissolved 3,5-trans-7-chloro-3-[1-(2-cyanoethyl)tetrazol-5-yl]methyl-5-(2,4-dimethoxyphenyl)-1-neopentyl-l,2,3,5-tetrahydro-4,1-25 benzothiazepin-2-one (59 mg). To the solution was added a IN aqueous solution of sodium hydroxide (0.11 ml), which was stirred for 6 hours at room temperature. To the reaction mixture was added water (50 ml). The solution was made acid, followed by extraction with 30 dichloromethane. The extract solution was washed with a saturated aqueous solution of ammonium chloride, which was then dried on anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from dichloromethane to give 26 mg of 35 colorless crystals, m.p.168-173°C. Elemental Analysis for C2,H28C1N503S: - 133 - 64 5 1 6 Calcd.: C, 57.42; H, 5.62; N, 13.95 Found : C, 57.28; H, 5.22; N, 13.84 Example 59 (3R, 5S)-7-Chloro-5-(2/3-dimethoxyphenyl)-1-neopentyl-3-(tetrazol-5-yl )methyl-l ,2,3,5-tetrahydro-4,1-benzothaizepin-2-one j^VOMe juc^J "=c1.is By employing (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl) -l-neopentyl-2-oxo-l ,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid, substantially the same procedure was taken as in the case of Example 58 to give the captioned compound. (1) 3-[(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetylamino]propionitrile 1H-NMR(CDC13) 6: 0.991(9H,s), 2.336(lH,dd,J=3.8, 14.8Hz), 2.54-2.63(2H,m), 2.938(lH,dd,J=10.6,14.8Hz), 3.217(lH,d,J=13.6Hz), 3.39-3.50(2H,m), 3.720(3H,s), 3.778(lH,dd,(J=3.8,10.6Hz), 3.892(3H,S), 4.455(lH,d,J=13.6Hz), 6.279(IH,s), 6.60-6.66(lH,br), 6.821(lH,d,J=l.8Hz), 6.981(lH,dd,J=1.4, 8.0Hz), 7.16-7.39(4H,m) (2) (3R,5S)-7-Chloro-3-[l-(2-cyanoethyl)tetrazol-5- y 1 ] methyl-5-(2,3-dimethoxyphenyl)-1-neopentyl-1,2,3,5-tetrahydro-4,l-benzothiazepin-2-one - 134 - 264 5 1H-NMR(CDCI3) 6: 0,962(9H,s), 2.97-3.17(4H,m), 3.473(lH,dd,J=10.6,14.6Hz), 3.729(3H,s), 3.902(3H,s), 4.020(lH,dd,J=3.6, 10.6Hz), 5 4.306(lH,d,J=14.0Hz), 4.74- 4.81(2H,m), 6.333(lH,s), 6.84-7.77(6Hfm) (3) (3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-3-(tetrazol-5-yl)methyl-l,2,3,5-tetrahydro-10 4,l-benzothiazepin-2-one m.p.139-144°C Elemental Analysis for C2<H28C1N503S: -•Calcd.: C, 57.42; H, 5.62; N. 13.95 Found : C, 57.55; H, 5.76; N, 13.78 15 Example 61 (3R,5S)-7-Chloro-5-(2-chlorophenyl)-3-(2-hydroxyethyl) 1-neopentyl-l,2,3,5-tetrahydro-4,1-benzoxazepine To tetrahydrofuran (20 ml) were added (3R,5S)t7-Chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,3,5-20 tetrahydro-4,l-benzoxazepine-3-acetic acid (2 g) and aluminum lithium hydride (0.4 g). The mixture was heated for 6 hours under reflux, to which was added water. Insolubles were then filtered off. The filtrate was concentrated, which was purified by means 25 of a silica gel column chromatography (hexane : acetic acid ethyl ester = 2:1 v/v as an eluent) to give 1.65 of non-crystalline solid matter. lH-NMR.(CDCl3) 6: 0.963(9H,s), 1. 69-1. 83 (2H,m), - 135 - 264 516 2.45(lH,br), 2.563(lH,d,J=14.6Hz), 3.090(lH,d,J=10.6Hz), 3.72-3 .84 (4H,m), 3.96-4.14(lH,m)) 6.344(lH,d,J=2. 4Hz ) , 6.596(111,3), 7.05-7.71(6H,m) Example 62 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-3-(tetrazol-5-yl)methylaminocarbonylmethyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine H n-n r J^conii^ J, r ■ n-N 10 To a dimethylformamide solution of 3,5-trans-7- chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid (0.2 g) obtained in Example 9 and aminoacetonitrile bisulfate (0.12 g) were added diethyl cyanophosphonate (0.12 g) 15 and triethylamine (0.14 ml). The mixture was stirred' for 40 minutes at 0°C. To the reaction mixture was added ice-water, which was extracted with acetic acid ethyl ester. The extract solution was washed with water, which was then dried over anhydrous sodium 20 sulfate. The solvent was distilled off, and the residue was recrystallized from hexane to give 0.19 g of 3,5-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-(cyanomethylaminocarbonylmethyl)-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine, m.p.233-234°C. To a 25 solution of this compound (0.2 g) in toluene (2 ml) were added trimethylsilyl azide (50 mg) and dibutyl tin(IV) oxide (33 mg). The mixture was stirred for 24 hours at temperatures ranging from 110 to 120°C. The 264516 - 136 - reaction mixture was concentrated, to which was added ethyl ether (20 ml), followed by washing with a dilute aqueous solution of sodium hydroxide. The aqueous layer was made acid with IN HC1, which was extracted 5 with acetic acid ethyl ester. The organic layer was washed with water and, then, dried over anhydrous sodium sulfate. The solvent was distilled off," and the residue was recrystallized from dichloromethane-hexane to give 0.21 g of colorless crystals, m.p.264-265°C. 10 Elemental Analysis for C24HZ6C12N602 • 0 . 8H2: Calcd.: C, 53.31; H, 5.00; N, 15.54 Found : C, 53.58; H, 5.14; N, 15.33 Example 63 7-Chloro-5-(2-chlorophenyl)-2,4-dioxo-l-neopentyl-15 2,3,4,5-tetrahydro-lH-l,5-benzodiazepine-3-acetic acid ethyl ester (1) 2 ', 5-Dichloro-2-neopentylaminod.lphenylamine To an ethanol (50 ml) solution of 2-amino-2',5-dichlorodiphenylamine (2.35 g) were added pival 20 aldehyde (1.21 ml) and acetic acid (0.67 g). The mixture was stirred for one hour at room temperature. To the reaction mixture was added sodium cyanoborohydride (0.97 g), which was stirred overnight. The reaction mixture was concentrated, to which was 25 added acetic acid ethyl ester (100 ml). The mixture was washed with water and, then dried over anhydrous sodium sulfate, followed by distilling off the solvent. - 137 - 264 5 1 6 The residue was purified by means of a silica-gel column chromatography (hexane:toluene=5:1 v/v as an eluent) to give 1.7 g of an oily compound. ^-NMR(CDCl3) 8: 0.89(9H,s), 2.86(2H,d,J=5.2Hz), 5 4 .08(lH,br), 5.66(lH,br), 6.5- 6.85(3H,m), 7•0-7.2(3H,m), 7 . 34(lH,dd,J=8.0,1.6Hz) (2) 7-Chloro-5-(2-chlorophenyl) ~2,4-dioxo-l-neopentyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine 10 To a tetrahydrofuran (25 ml) solution of 2',5- dichloro-2-neopentylamihodiphenylamine (3.7 g) was added dropwise a tetrahydrofuran (5 ml) solution of malonyl dichloride (1.33 ml) at 0°C. The mixture was stirred for one hour at room temperature, then for two 15 hours at 60°C. The reaction mixture was concentrated, to which was added acetic acid ethyl ester (100 ml). The mixture was washed with water, then dried over anhydrous sodium sulfate, followed by distilling off the solvent. The residue was purified by means of a 20 silica gel column chromatography (hexane : acetic acid ethyl ester = 2:1 v/v as an eluent) to give 1.20 g of colorless crystals, m.p.245-246°C. Elemental Analysis for C2oH2oCl2N202: Calcd.: C, 61.39; H, 5.15; N, 7.16 25 Found : C, 61.10; H, 5.04; N, 6.99 (3) 7-Chloro-5-(2-chlorophenyl)-2,4-dioxo-l-neopentyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine-3-acetic acid ethyl ester To a solution of 7-chloro-5-(2-chlorophenyl)-2,4-30 dioxo-l-neopentyl-2,3,4,5-tetrahydro-lH-l,5- benzodiazepine (0.3 g) and chloroacetic acid ethyl ester (0.11 ml) in dimethylformamide (2 ml) was added sodium hydride (60% oil, 40 mg), and the mixture was stirred for 30 minutes at room temperature. To the 35 reaction mixture were further added sodium hydride (40 mg x 3) and chloroacetic acid ethyl ester (0.11 ml), 138 264 5 1 6 which was stirred for 3 hours. To the mixture was then added acetic acid ethyl ester (50 ml), which was washed with water. The solvent was distilled off, and the residue was purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester = 4:1 v/v as an eluent) to give 0.25 g of colorless crystals, m.p.152-153°C Elemental Analysis for C2<H26C12N204: Calcd.: C, 60.38; H, 5.49; N, 5.87 Found : C, 60.22; H, 5.61; N, 6.05 Example 64 7-Chloro-5-(2-chlorophenyl)-2,4-dioxo-l-neopentyl-2,3,4-, 5-tetrahydro-lH-l, 5-benzodiazepine-3-acetic acid 7-Chloro-5-(2-chlorophenyl)-2,4-dioxo-1-neopentyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine-3-acetic acid ethyl ester (0.2 g) obtained in Example 63 was subjected to substantially the same procedure as in Example 57 to give 0.18 g of colorless crystals, m.p.282-285°C Elemental Analysis for C22H22CI2N2O4: Calcd.: C, 58.81; H, 4.94; N, 6.23 Found : C, 58.71; H, 5.15; N, 6.21 Example 65 (3R,5S)-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid sodium salt - 139 - 2 6 4 5 1 6 OMe C K^COffNa* N~< In methanol (50 ml) was dissolved (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid (1.275 g) obtained in Example 51. To the solution was added IN aqueous solution of sodium hydroxide (2.57 ml), which was concentrated. The concentrate was washed with acetic acid ethyl ester to give 1.23 g of colorless crystals melting at not lower than 300°C [a]D2* -267.7° (c=0. 64, MeOH) Elemental Analysis for C2«H27ClN05SNa. 0. 7H20: Calcd.: C, 56.24; H, 5.58; N, 2.73 Found : C, 56.16; H, 5.80; N, 2.81 Example 6 6 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester To a solution of 3,5-trans-7-chloro-5-(2-chlorophenyl)-2-oxo-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (0.5 g) in dichloromethane (5 ml) was added tetrabutylammonium borohydride (0.96 g). The mixture was refluxed for 7 264 5 1 6 hours. The solvent was distilled off. To the residue was added IN HCl (8 ml) and the mixture was refluxed for 10 minutes. The solution was neutralized with a IN aqueous solution of sodium hydroxide, which was 5 extracted with dichloromethane. The extract solution was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was'purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester = 3:1 v/v as an eluent) to give 10 0.13 g of a colorless oily product. 1H-NMR(CDC13) 6 : 2.97(lH,dd,J=5.8,16.0Hz), 3.20(lH,dd,J=8.0,16.0Hz), 3.26(lH,dd,J=2.4,13.4Hz ), 3.35-3.42(lH,m), 3.61(lH,dd,J=4.8,13.4Hz), 3.68(3H,s), 5.96(IH,s), 6.55(IH,d,J=2.2Hz), 6.83(lH,d,J=8.2Hz ), 15 7.03(lH,dd,J=2.4,8.2Hz), 7.28-7.56(4H,m) Example 67 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid ethyl ester O-Cl ixxy^ (1) 5-Chloro-2-(2,4-dimethoxybenzylamino)-a-(2-20 chlorophenyl)benzyl alcohol 2-Amino-5-chloro-a-(2-chlorophenyl)benzylalcohol (20 g) and 2,4-dimethoxybenzaldehyde (12.5 g) were subjected to substantially the same procedure as in Example 30 to give 33 g of an oily compound. 25 1H-NMR(CDC13) 6 : 3.75(3H,s), 3.76(3H,s), 4.23(2H,s), 6.10(IH,s), 6.35-6.44(2H,m), 6.63(lH,d,J=8.8Hz), 6.88(lH,d,J=2.6Hz), 7.03-7.12(2H,m), 7.24-7.45(4H,m) (2) 3-[N-[4-Chloro-2-(2-chloro-a-hydroxybenzyl)phenyl]-N-(2,4- 30 dimethoxybenzyl)carbamoylacrylic acid ethyl ester - 141 - 264 5 1 6 5-Chloro-2- (2,4-dimethoxybenzylami.no) -a- (2-chlorophenyl)benzyl alcohol (33 g) and fumaric chloride monoethyl ester (12.8 g) were subjected to substantially the same procedure as in Example 30 to 5 give 48.9 g of an oily compound. ^-NMR(CDC13) S : 1.18-1.35(3H,m), 3.46(3H,s), 3.78(3H/s),' 3.82,3.83(2H, each s), 3.94-4.34(2H,m), 4.64(l/2xlH,d,J=14.2Hz), 5.48(l/2xlH,d,J=14.2Hz), 6.02-8.00(12H,m) 10 (3) 3,5-trans-7-Chloro-5-(2-chlorophenyl)-l-(2,4-dimethoxybenzyl)-2-oxo-l,2,2,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester --To a solution of the compound (48.9 g) obtained in (2) in ethanol'(500 ml) was added potassium carbonate 15 (12.4 g). The mixture was stirred overnight at room temperature. The solvent: was distilled off. To the residue was added dichloromethane (200 ml), which was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the 20 residue was recrystallized from a mixture solvent of dichloromethane-hexane to give 41.4 g of colorless crystals, m.p.135-136°C. (4) 3,5-trans-7-Chloro-5-(2-chlorophenyl)-2-oxo- l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid 25 ethyl ester The compound (5 g) obtained in (3), potassium persulfate (10 g) and dipotassium hydrogenphosphate (3.3 g) were added to a mixture solvent of acetonitrile (80 ml) and water (40 ml), which was refluxed for 2 30 hours. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract solution was dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by means of a silica-gel column chromatography (hexane:acetic 35 acid ethyl ester = 3:1 v/v as an eluent) to give 1.83 g of colorless crystals, m.p.132-137°C. - 142 - 26451 6 (5) 3,5-trans-7-Chloro-5-(2-chlorophenyl)-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetic acid ethyl ester The compound (1.8 g) obtained in (4) was subjected 5 to substantially the same procedure as in Example 66 to give 0.69 g of a colorless oily product. 1H-NMR(CDC13) 6 : 1.14(3H,t,J=7.2Hz), 2.54(lH,dd,J=6.6,15.0Hz), 2.73(lH,dd,J=7.4,15.0Hz ), 3.29-3.32(2H,m), 4.05(2H,q,J=7.2Hz), 4.20-4.32(lH,m), 10 6.33(IH,s), 6 . 64(lH,d,J=2.4Hz), 6.72(lH,d,J=8.4Hz), 7.04-7.43(5H,m) Example 6 8 3.5-trans-7-Chloro-5-(2-chlorophenyl)-1-propyl-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl 15 ester To a solution of 3,5-trans-7-chloro-5-(2-chlorophenyl)-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester (0.1 g) obtained in Example 66 in methanol (2 ml) were added propionaldehyde (76 mg) 20 and acetic acid (24 mg). The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added sodium cyano borohydride (25 mg), which was stirred for further one hour at room temperature. To the reaction mixture was added 25 dichloromethane (50 ml), which was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 0.13 g of a colorless oily product. 1H-]OTIR(CDCl3 ) 5 : 0 . 99 ( 3H, t, J=7 . 4Hz), 1. 46-1. 63 ( 2H,m) , 30 2.76-3.05(5H,m), 3.24-3.46(2H,m), 3.68(3H,s), 143 2645 16 6.43(lH,s), 6.53(lH/d,J=2.4Hz), 7.05-7.42(5H,m), 7.73-7 . 77 (lH,m) Example 6 9 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-propyl-l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid ethyl ester "*3,5-trans-7-Chloro-5- (2-chlorophenyl) -1,2,3,5-tetrahydro-4-, l-benzoxazepine-3-acetic acid ethyl ester (0.1 g) obtained in Example 67 was subjected to substantially the same procedure as in Example 68 to give a colorless oily product (0.06 g). ^-NMR(CDC13) S : 0.98(3H,t,J=7.2Hz), 1.19(3H,t,J=7.2Hz), 1.57-1.74(2H,m), 2.53(lH,dd,J=5.8, 15.0Hz), 2.74(lH,dd,J=7.6,15.0Hz), 2.92-3.06(2H,m), 3.27-3.47(2H,m), 4.10(2H,dq,J=1.4,7.2Hz), 4.17-4.25(lH/m)r 6.39(lH,d,J=2.4Hz), 6.43(lH,s), 6.90(lH,d,J=8.6Hz), 7.14(lH,dd,3=2.6,8.6Hz), 7.28-•7 . 63 (4H,m) Example 70 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-propyl-l,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid hydrochloride j-l HC1 CH5 - 144 - 26451 6 To a solution of 3,5-trans-7-chloro-5-(2-chlorophenyl)-1-propyl-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (0.13 g) obtained in Example 68 in dioxane (1 ml) was added 6N 5 HCl (1 ml), and the mixture was refluxed for 30 minutes. The solvent was distilled off, and the residue was recrystallized froih ethanol-hexane to give 57 mg of colorless crystals, m.p.l65-168°C. Elemental Analysis for C20H21Cl2NO2S .HCl • 0 . 3H20: 10 Calcd.: C, 53.12; H, 5.04; N, 3.10 Found : C, 53.21; H, 5.03; N, 3.34 Example 71 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-propyl-l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid 15 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-propyl- 1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid ethyl ester (0.15 g) obtained in Example 69 was subjected to reaction in substantially the same manner as in Example 70 to give 50 mg of colorless crystals, 20 m.p.105-112°C. Elemental Analysis for C20H21Cl2NO3.HCl. 0. 6H20: Calcd.: C, 54.40; H, 5.30; N, 3.17 Found : C, 54.33; H, 5.37; N, 3.31 Example 7 2 25 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-propionyl- 1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester 26451 - 145 - 1 xx> y^COOCHg no To a solution of 3,5-trans-7-chloro-5-(2-chlorophenyl)-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid methyl ester (100 mg) obtained in Example 66 in dichloromethane (2 ml) was added sodium hydrogencarbonate (59 mg). To the mixture was further added" propionyl chloride (60 mg). The mixture was stirred for 2 hours at room temperature, to which was added dichloromethane (50 ml). The mixture was washed with water, then the solvent was distilled off. The residue was recrystallized from ethyl ether - petroleum ether to give 90 mg of colorless crystals, m.p.191-194°C. ^-NMR(CDCl3) 8 : 1.14(3H,t,J=7.2Hz), 2.07-2.33(2H,m), 2 . 83(lH,dd,J=7.6,16.8Hz), 3.02(lH,dd,J=7.2,16.8Hz ), 3.24(lH,dd,J=3.0,13.6Hz), 3.32-3.44(lH,m), 3.68(3H,s), 4.85(lH,dd,J=5.0,13.6Hz), 6.00(lH,s), 6.60(lH,d,J=2.2Hz), 7.11-7.63(6H,m) Example 73 3>5-trans-7-Chloro-5-(2-chlorophenyl)-1-propionyl-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid ethyl ester CH3 5 10 15 20 25 26 A 5 1 6 - 146 - 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid ethyl ester (100 mg) obtained in Example 67 was subjected to substantially the same procedure as in Example 72 to give 70 mg of an oily product. 1H-NMR(CDC13) 6 : 1.07(3H,t,J=7.0Hz), 1.16(3H,t,J=7.4Hz), 2.14-2.52(2H,m), 2.61(1H,dd, J=5 .4,15. 4Iiz) , 2 . 88 (lH,dd, J=9 . 2,15. 4Hz ), 3.25(lH,dd,J=3.2,13.6Hz), 3.85-4.16(2H,m), 4.24-4.40(lH,m), 4.56(lH,dd,J=6.0; 13.6Hz), 6.29(lH,s), 6.50(lH,d,J=2.2Hz), 7.16-7.68(6H,m) Example 7 4 3,5-t-rans-7-Chloro-5-(2-chlorophenyl)-1-propionyl-1,2,3,5-tetrahydro-4,l-benzothiazepine-3-acetic acid To a solution of 3,5-trans-7-chloro-5-(2-chlorophenyl)-l-propionyl-l,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (90 mg) obtained in Example 72 in dioxane (2 ml) was added 2N HCl (1 ml). The mixture was refluxed for 2 hours, to which was added dichloromethane (50 ml). The mixture was washed with water, then the solvent was distilled off. The residue was recrystallized from ethyl ether -hexane to give 52 mg of colorless crystals, m.p.230-232°C. Elemental Analysis for C20H19Cl2NO3S: Calcd.: C, 56.61; H, 4.51; N, 3.30 Found : C, 56.26; H, 4.65; N, 3.51 Example 75 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-propionyl-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid - 147 - 264516 r\ 3 ,5-trans-7-Chloro-5-(2-chlorophenyl)-1-propionyl-1,2,3,5-tetrahydro-4, l-benzoxazepine-3-acetic aci.d ethyl ester (70 mg) obtained in Example 7 3 was subjected to substantially the same procedure as in 5 Example 74 to give 43 mg of colorless crystals, m.p.l87-190°C. Elemental Analysis for C2oH19Cl2NO/i: Calcd.: C, 58.84; H, 4.69; N, 3.43 Found : C, 58.75; H, 4.67; N, 3.59 10 Example 76 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid tert-butyl ester cxci (1) 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-15 2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid tert-butyl ester To a solution of 3,5-trans-7-chloro-5-(2-chlorophenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (2 g) in dichloromethane 20 (20 ml) were added isobutene (1 ml) and conc. sulfuric acid (0.05 rag). The mixture was left standing for 24 hours in a sealed vessel. The solution was washed with 2 6 4 5 16 - 148 - water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica-gel column chromatography (hexane : acetic acid ethyl ester = 5:1 v/v as an eluent) to 5 give 1.67 g of colorless crystals, m.p.145-147°C. (2) 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid tert-butyl ester To a dichloromethane solution of the compound (1_. 10 g) obtained in (1) was added tetrabutylammonium borohydride (1.57 g). The mixture was then subjected to substantially the same procedure as in Example 66 to give-0.52 g of a colorless oily product. 1H-NMR(CDC13) S : 0.95(9H,s), 1.44(9H,s), 15 2.33(lH,dd,J=5.0, 15.4Hz), 2.55(lH,dd,J=7.8,15 . 4Hz ) , 2.56(lH,d,J=13.2Hz), 3.09(lH,dd,J=1.8,11.2Hz), 3.63-3.78(2H,m), 4.12-4.26(lH,m), 6.32(lH,s), 6.59(lH,s), 7.11-7.76(6H,m) Example 77 20 3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid J ^COOH To a solution of 3,5-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-l,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid tert-butyl ester (0.5 g) 25 obtained in Example 7 6 in dioxane (5 ml) was added 2N aqueous hydrogen chloride solution (1 ml). The mixture was refluxed for 3 hours under reflux. The reaction mixture was neutralized with IN NaOH, to which was added dichloromethane (100 ml), followed by washing 26 4 5 i - 149 - with water. The solvent was distilled off. The residue was purified by means of a silica-gel column chromatography (dichloromethane:methanol:water=0:1:0.1 v/v as an eluent) to give 85 mg of colorless crystals, 5 m.p.195-208°C. Elemental Analysis for C22H25Cl2N03. 0 . 2H20: Calcd.: C, 62.04; H, 6.01; N, 3.29 Found : C, 62.14; H, 6.01.; N, 3.42 Assay Method of Squalene Synthetase Inhibitory Activity 10 The squalene synthetase inhibitory activity was assayed as follows with the enzyme solutions described in the subsequent Experimental Examples 1 and 2. -More specifically, an enzyme solution (protein content 0.8 ug) prepared in Experimental Example 1 or 2 15 was added to a solution (total volume 50 ) ) containing 5 uM [1-3H] farnesyl pyrophosphate (specific activity 25 uCi/mole), 1 mM NADPH, 5 mM MgCl2, 6 inM glutathione, a 100 mM buffer solution of potassium phosphate (pH 7.4) and a test drug (used as an aqueous 20 solution or a DMSO solution), then the reaction was allowed to proceed at 37°C for 45 minutes. To the reaction mixture was added 150 p.4 of a mixture of chloroform and methanol (1:2) to suspend the reaction, followed by adding 50 of chloroform and 50 n<! of a. 25 3N aqueous solution of sodium hydroxide. 50 of the chloroform layer (lower layer) containing the reaction mixture having squalene as the principal component and 3 ml of toluene-based liquid scintillator were mixed, and its radioactivity was determined by means of a 30 liquid scintillation counter. The squalene synthetase inhibitory activity was expressed in terms of the concentration inhibiting by 50% the radioactivity taken into the chloroform layer (IC50, molar concentration (M)). 35 Experimental Example 1 Preparation of rat-derived enzyme 5 10 15 20 25 6 U "f J I - 150 - An SD male rat (6 week old) was killed by-bleeding, and its liver was excised. About 10 g of the liver was washed with a saline solution cooled with ice, which was then homogenized in 15 ml of an ice-cooled buffer solution [100 mM potassium phosphate (pH 7.4), 15 mM nicotinamide, 2 mM MgCl2], followed by centrifugation for 20 minutes (4°C) with 10000 x g. The supernatant layer was separated and subjected to further centrifugation for 90 minutes (4 °C) at 105000 x g. The sediment was then suspended in an ice-cooled 100 mM phosphate buffer solution (pH 7.4), which was again subjected to centrifugation for 90 minutes (4°C) at 10-5000 x g. The sediment thus obtained (microsome fraction) was suspended in an ice-cooled 100 mM potassium phosphate buffer (pH 7.4) (about 40 mg/ml protein concentration, determined with BCA protein assay kit of Pias Co., Ltd.). This suspension was used as the enzyme solution. Experimental Example 2 Preparation of human-derived enzyme Human hepatic carcinoma cells HepG2 (about 1 x 109 cells) obtained by incubation in a Dulbecco-modified Eagle's medium (37°C in the presence of 5% C02) were suspended in 10 ml of an ice-cooled buffer solution [100 mM potassium phosphate buffer (pH 7.4), 30 mM nicotinamide and 2.5 mM MgCl2] • The cells were crashed by means of ultrasonication (for 30 seconds, twice). From the sonicate thus obtained, the microsome fraction was obtained by the same procedure as in Experiment Example 1, which was suspended in an ice-cooled 100 mM potassium phosphate buffer (pH 7.4) (about 4 mg./ml / protein concentration). This suspension was used as. the enzyme solution. The results are shown in.[Table 4]. • " - 151 - 2 6 4 5 16 [Table 4] Compound No. Rat-derived enzyme (10~7M) Human-derived enzyme (10"7M) Examples 8-1 20 9 1.8 0.39 10-2 0.62 0.42 10-3 9.2 10-4 1.0 10-5 0.51 0.25 10-6 0.39 0.31 10-7 0.26 0.13 10-8 0.23 0.13 13 39 14 4.3 1.6 19 7.0 21 33 23 0. 22 0.13 26 3.9 1.2 28 4.6 31 1.7 33 0.88 0.73 34 >10 36 4.9 43 0.093 0.059 44 9.6 50 >10 51 0.21 0.18 53 2.9 1.3 59 0.16 0.10 - 152 - 264 5 1 6 Formulation Examples A squalene synthetase inhibiting agent containing, as its effective component, a compound represented by the formula (I), (I'), (I'') or (I''') of this invention or a salt thereof, in the case where it is used as a therapeutic agent of hypercholesteremia, can be formulated in accordance with, for example, the following prescriptions. 1. Capsules (1) Compound obtained in Example 10-8 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg -.(4) Magnesium stearate 10 mg One capsule 180 mg (1), (2) and (3) and one half of (4) were blended and the mixture was granulated, to which was added the balance of (4). The mixture was filled in a gelatin capsule. 2. Tablets (1) Compound obtained in Example 10-8 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet 230 mg (1), (2) and (3) and two thirds of (4) and one half of (5) were blended and the mixture was granulated, to which were added the balance of (4) and (5). The mixture was subjected to compression-molding to provide tablets. 3. Injections (1) Sodium salt of the compound obtained in Example 10-8 10 mg (2) Inositol 100 mg (3) Benzyl alcohol 20 mg One ampoule 130 mg </div>

Claims

<div class="application article clearfix printTableText" id="claims"> <16 4 5 1 - 153 - (1), (2) and (3) were dissolved in distilled water for injection to make the whole volume 2 ml, which was put in an ampoule, and the ampoule was sealed. All the processes \-ere conducted under sterilized conditions;. 5 4. Capsules (1) Compound obtained in Example 9 10 mg (2) Lactose SO mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 10 One capsule 100 mg (1), (2) and (3) and one half of (4) were blended and the mixture was granulated, to which was added the balance of (4). The mixture was filled in a gelatin capsule. 15 5. Tablets (1) Compound obtained in Example 9 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet 230 mg (1), (2) and (3) and two thirds of (4) and one half of (5) were blended and the mixture was granulated, to which were added the balance of (4) and 25 (5).. The mixture was subjected to compression-molding to provide tablets. 6. Injections (1) Sodium salt of the compound obtained in Example 9 10 mg 30 (2) Inositol 100 mg. (3) Benzyl alcohol 20 mg One ampoule 13.0 mg (1), (2) and (3) were dissolved in distilled.water for injection to make the whole volume 2 ml, which was 35 put in an ampoule, and the ampoule was sealed. All the processes were conducted under sterilized conditions. - 154 - 264516 WHAT WE CLAIM IS:- 1. A compound of the formula (I) : R\ (TQ-r •. (I) r/ wherein Ri is hydrogen or an optionally substituted hydrocarbon group; R2' is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X' is a group represented by the formula X-Y wherein X is a bond or a divalent atomic chain represented by the formula —^CH2 ^m~E~^ CH*rT~ wherein m and n independently denote 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHCO-, -CON(R5)- or -NHCONH-; wherein R4 and R5 independently stand for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group, when n is 2 or 3 each R4 may be the same or different; and R3 stands for H, a lower alkyl group, aralkyl group or acyl group; an optionally esterified carboxyl group; an optionally substituted carbamoyl group; an hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted aryloxy group or an optionally substituted aralkyloxy group; an optionally substituted amino group; or an optionally substituted heterocyclic radical having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Ring is a 7-membered heterocyclic ring containing at most three ring constituting hetero atoms; D is optionally substituted j N.Z. PATENT OFFICE (followed|by Y is (.i) (ii) (iii) (iv) (v) 264516 - 154a - C or N; Z]_ is optionally substituted C, N, C=0, S(0)g (q=0, 1 or 2) or 0; D-Zi may be a single bond or a double bond; K is optionally substituted C or N; the ring optionally having, besides , R2' and X', a further substituent, provided that the condensed ring composed of Ring A and Ring Ji is not 2-oxo-l,2,3,5-tetrahydro-4,1-benzoxazepine ring, 2-oxo-l>4-benzodiazepine, 1,4-benzodiazepine ring or 2,4-dioxo-2,3,4,5-tetrahydro-lH-1,5-benzodiazepine ring, or a salt thereof. 2. The compound or the salt thereof as claimed in claim 1, in which the compound is represented by the formula (I'): (followed by page 155) • N.Z. PATFNT OFFICE 2 1 B£C 1335 1 155 264516 Hi' g&V K—^ (I') wherein Rj is hydrogen or an optionally substituted hydrocarbon group; R2' is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X' is a group represented by the formula X-Y wherein X is a bond or a divalent atomic chain represented by the formula ^CH2^m~E~^CH^n~ wherein m and n independently denote 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHC0-, -CON(R5)- or -NHCONH-; wherein R4 and R5 independently stand for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group, when n is 2 or 3 each R4 may be the same or different; and R3 stands for H, a lower alkyl group, aralkyl group or acyl group; Y is (i) an optionally esterified carboxyl group; (ii) an optionally substituted carbamoyl group; (iii) an hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted aryloxy group or an optionally substituted aralkyloxy group; (iv) an optionally substituted amino group; or (v) an optionally substituted heterocyclic radical Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Ring J2 is a 7-membered heterocyclic ring; Z2 is S(0)g (q=0, l or 2), optionally substituted C, C=0, or 0; K is optionally substituted C or N; G is 0 or S, provided that the condensed ring composed of Ring A and Ring J2 is not 2-oxo-l,2,3,5-tetrahydro-4,1-benzoxazepine ring, or a salt thereof. having a protonizable hydrogen; * .-J.Z. PATFMT OFFICE (followed 26451 - 155a - 3. The compound or the salt thereof as claimed in Claim 1 or 2, in which RL is an aliphatic chain hydrocarbon group. 4. The compound or the salt thereof as claimed in Claim 3, in which Rx is an alkyl group. 5 . The compound or the salt thereof as claimed in Claim 1 or 2, in which R2' is a substituted phenyl group. 6. The compound or the salt thereof as claimed in 264516 Claim 1 or 2, in which X' is an alkyl substituted with an optionally esterified carboxyl group. 7. The compound or the salt thereof as claimed in Claim 1 or 2, in which X' is an alkyl substituted with an optionally substituted heterocyclic radical having a protonizable hydrogen. 8. The compound or the salt thereof as claimed in Claim 1, in which the heterocyclic residue is N—« H H H v^o or "va 9. The compound or the salt thereof as claimed in Claim 6 or 7, the alkyl is a straight-chain Cj_4 alkyl. 10. The compound or the salt thereof as claimed in Claim 1 or 2, in which the aromatic heterocyclic ring represented by Ring A is on . Till. The compound or the salt thereof as claimed in Claim 1, in which the substitutent of Ring is oxo or thioxo. 12. The compound or the salt thereof as claimed in. Claim 1, in which the condensed ring composed of ring A and ring Ji is 264516 0c3 . oct cc?', oo . co . co. cO or sO 13. The compound or the salt thereof as claimed in Claim 2, in which Z2 is S(0)q (q=0, 1 or 2). 14. The compound or the salt thereof as claimed in. Claim 2, in which K is C. 15. A squalene synthetase inhibitor which comprises the compound represented by the formula (I): wherein Ri is hydrogen or an optionally substituted hydrocarbon group; R2' is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X' is a group represented by the formula X-Y wherein X is a bond or a divalent atomic chain represented by the formula —^CH2^m~E~^CH^n~ wherein m and n independently denote 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHCO-, -CON(R5)- or -NHCONH-; wherein R4 and R5 independently stand for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group, when n is 2 or 3 each R4 may be the same or different; and R3 stands for H, a lower alkyl group, aralkyl group or acyl group^*™ 'ATENT OFFfCF 2 i (followed by page 157a) 26451ff - 157a - Y is (i) an optionally esterified carboxyl group; (ii) an optionally substituted carbamoyl group; (iii) an hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted aryloxy group or an optionally substituted aralkyloxy group; (iv) an optionally substituted amino group; or (v) an optionally substituted heterocyclic radical having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Ring is a 7-membered heterocyclic ring containing at most three ring constituting hetero atoms; D is optionally substituted C or N; Z]_ is optionally substituted C, N, C=0, S(0)q (q=0, 1 or 2) or 0; D-Z]_ may be a single bond or a double bond; K is optionally substituted C or N; the ring J_-]_ optionally having, besides R^, R2' and X', a further substituent, provided that the condensed ring composed of Ring A and Ring J]_ is not 2-oxo-l, 2, 3 , 5-tetrahydro-4 ,1-benzoxazepine ring, 2-oxo-l,4-benzodiazepine, 1,4-benzodiazepine ring or 2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine ring, or a pharmaceutically acceptable salt thereof. (followed" by 2 1 DEC 264516 158 16. The inhibitor as claimed in Claim 15, in which RL is an aliphatic chain hydrocarbon group. 17. The inhibitor as claimed in Claim 16, in which Ri is an alkyl group. 18. The inhibitor as claimed in claim 15, in which R2' is a substituted phenyl group. 19. The inhibitor as claimed in claim 15, in which X' is an alkyl substituted with an optionally esterified carboxyl group. 20. The inhibitor as claimed in claim 15, in which X' is an alkyl substituted with an optionally substituted heterocyclic radical having a protonizable hydrogen. 21. The inhibitor as claimed in Claim 20, in which the heterocyclic residue is KT OFFICE 1 DEC 1395 26451 - 159 - 22. The inhibitor as claimed in Claim 19 or 20, in which th^= alkyl is a straight-chain C^ alkyl. 23. The inhibitor as claimed in Claim 15, in which the aromatic heterocyclic ring represented by Ring A is ft . ft ftj h- 24. The inhibitor as claimed in Claim 15, in which the substitutent of Ring J' is oxo or thioxo. 25. The inhibitor as claimed in Claim 15, in which the condensed ring composed of Ring A and Ring J' is / o0 . oO . 00 . 00' . 00 . 00- . 00" . 00 . 00 " g0 26. The inhibitor as claimed in Claim 15, in which the compound is represented by the formula i.r;: xTEN'T OFFTCE 2 1 DEC '985 - 160 - 264 5 1 6 wherein. RA is hydrogen or an optionally substituted hydrocarbon group; R2 is hydrogen, an optionally substituted alk^l group, an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; is a bond or a divalent atomic chain represented by the formula ^4 ~4CH2)m"E"(CH^T wherein m and n independently denote 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHCO-, -CON(R5)- or -NHCONH-; wherein R4 and R5 independently stand for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group, when n is 2 or 3 each R4 may be the same or different; and R3 stands for H, a lower alkyl group, aralkyl group or acyl group- Y is (i) an optionally esterified carboxyl group; (ii) an optionally substituted carbamoyl group; (iii)a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted aryloxy group; (iv) an optionally substituted amino group; or (v) an optionally substituted heterocyclic radical having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Z3 is =N"-, -N(R7)- (wherein R7 stands for H, alkyl group or acyl group), -S-, -S(0)-, -s(0)2~, -CH2- or -0-; G is 0 or S; the symbol is a double bond when Z3 is =N-, while a single bond when Z3 is not =N-, provided that, when Z3 is -0- and Ring A is an optionally substituted benzene ring, G is S, or a pharmaceutically acceptable salt thereof. 27. The inhibitor as claimed in claim 26, in which Z3 is S(0)<, (q«0., 1 or 2). - H ^ 26 4 5 16 161 28. The compound (3R)-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-3-acetic acid methyl ester. 29. The compound (3R)-1-isobutyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid methyl ester. 30. The compound (3R)-1-isobutyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-3-acetic acid. 31. The compound (3R,5S)-l-isobutyl-7-chloro-5-(2-chlorophenyl) - 2, 3,4,5-1etrahydro-2-oxo-IH-1,4-benzodiazepine-3 -acetic acid. 32. The compound (3S)-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH-1,4-benzodiazepine-3-acetic acid methyl ester. 33. The compound (3S)-1-isobutyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-3-acetic acid methyl ester. 34. The compound (3S)-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-isobutyl-2-oxo-IH-1,4-benzodiazepine-3 -acetic acid. 35. The use of. a compound of the formula (I ) : * wherein is hydrogen or an optionally substituted hydrocarbon group; R2' is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X' is a group represented by the formula X-Y wherein X is a bond or a divalent atomic chain (I) Intellectual Property Office of NZ - 6 JAN 1998 received - 162 - 264 5 16 • 4 represented by the formula —fcCH'j)m~E—CH^n~ -wherein m and n independently denote 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone, -N(R3)-, -NHCO-, -CON(R5)- or -NHCONH-; wherein R4 and R5 independently stand for H, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group, when n is 2 or 3 each R4 may be the same or different; and R3 stands for H, a lower alkyl group; aralkyl group or acyl group; Y is (i) an optionally esterified carboxyl group; (ii) an optionally substituted carbamoyl group; (iii) an hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted aryloxy group or an optionally substituted aralkyloxy group; (iv) an optionally substituted amino group; or (v) an optionally substituted heterocyclic radical' having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Ring is a 7-membered heterocyclic ring containing at most three ring constituting hetero atoms; D is optionally substituted C or N; Z]_ is optionally substituted C, N, C=0, S(0)q (q=0, 1 or 2) or 0; D-Z]_ may be a single bond or a double bond; K is optionally substituted C or N; the ring optionally having, besides R]_, R2' and X', a further substituent, provided that the condensed ring composed of Ring A and Ring Ji is not 2-oxo-l,2,3, 5-tetrahydro-4,1-benzoxazepine ring, 2-oxo-l,4-benzodiazepine, 1,4-benzodiazepine ring or 2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine ring, Intellectual Property Office of NZ -6 JAN 1998 Received 264 518 163 - or a pharmaceutical^ acceptable salt thereof, in the manufacture of a medicament for use as a squalene synthetase inhibitor. , forth in claim 35 wherein the medicament is' for the treatment of hypercholesteremia in humans. i 37. A compound as claimed in claim 1 as specifically set forth herein. 38. A process for producing a compound as claimed in claim 1 ; substantially as herein described with reference to the Examples. 39. The use as claimed in claim 35 or claim 36 substantially j as herein described. 36. The use of a compound of the formula (I ) as set INDUSTRIES. INC. END OF CLAIMS ,nte»ectual Property Office of NZ "6 JAN 1998 received </div>